Diagnostic Applications of Nuclear Medicine: Lymphomas
Hodgkin and non-Hodgkin lymphomas are lymphoid neoplasms arising from B cells, T cells, or NK (natural killer) cells. [18F]FDG PET/CT is more accurate for the primary staging of lymphoma, particularly because it can detect disease in normal-sized lymph nodes, liver, spleen, and bone marrow. A major advantage of [18F]FDG PET in determining the outcome of therapy is distinguishing active lymphoma from fibrosis/necrosis in residual masses. Posttherapy [18F]FDG PET provides important prognostic information and has been incorporated into the currently used criteria for evaluating response to therapy in lymphoma (Lugano/Lyric Classifications). Interim [18F]FDG PET/CT also provides prognostic information and is being evaluated for “risk-adapted therapy” in setting of clinical trials.
KeywordsLymphoma FDG-PET/CT FDG Hodgkin non-Hodgkin NHL Nuclear
Therapy with adriamycin, bleomycin, vinblastine, and dacarbazine
Autologous stem cell transplantation
Therapy with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and procarbazine
Classical Hodgkin lymphoma
Therapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone
Chronic lymphocytic leukemia
X-ray computed tomography
Diffuse large B-cell lymphoma
Epstein-Barr herpesvirus (EBV)
Eastern Cooperative Oncology Group
European Organisation for Research and Treatment of Cancer
- EPOCH-R (or R-EPOCH)
Therapy with rituximab, etoposide, prednisolone, oncovin (vincristine), cyclophosphamide, and hydroxydaunorubicin (doxorubicin)
Therapy with etoposide, prednisolone, oncovin (vincristine), cyclophosphamide, and hydroxydaunorubicin (doxorubicin)
International Prognostic Index for follicular Hodgkin lymphoma
Granulocyte colony-stimulating factor
Gene expression profiling
Hematopoietic cell transplantation
Therapy with ifosfamide, carboplatin, and etoposide
Involved-field radiation therapy
International Prognostic Index
International Prognostic Score
International Working Group
Lymphocyte-predominant Hodgkin lymphoma
Mucosa-associated lymphoid tissue
Therapy with mechlorethamine, vincristine, procarbazine, and prednisone
Minimal residual uptake
National Comprehensive Cancer Network
Non-Hodgkin lymphoma (NHL)
- NK cell
Natural killer cells
Negative predictive value
Polymerase chain reaction
Positron emission tomography
Positron emission tomography/Computed tomography
Positron emission tomography guided therapy of aggressive lymphomas
Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone
- R-EPOCH (or EPOCH-R)
Therapy with rituximab, etoposide, prednisolone, oncovin (vincristine), cyclophosphamide, and hydroxydaunorubicin (doxorubicin)
Therapy with rituximab, ifosfamide, carboplatin, and etoposide
- RS cell
Radiological Society of North America
Small lymphocytic lymphoma
Standardized uptake value
White blood cell
Lymphoma is a hematologic malignancy characterized by abnormal proliferation of lymphoid cells (i.e., lymphocytes, histiocytes), most commonly arising in lymph nodes, but potentially involving any organ or tissue in the body. There are two major classifications of lymphomas that are determined by distinct morphologic features: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Diagnostic nuclear medicine procedures, in particular 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography/computed tomography (FDG-PET/CT), have emerged in the past two decades as an integral component in the evaluation of many patients with lymphoma to optimize therapeutic strategies.
Investigators began studying the use of FDG-PET in patients with lymphoma in the late 1980s . Initial studies showed great benefit and promise from metabolic tumor imaging, but the lack of anatomic information was a limitation. FDG-PET detected more lesions than CT . In 2001, combined PET/CT scanners were introduced for widespread clinical use, and the power of the hybrid imaging technique was soon realized. Current roles of FDG-PET and PET/CT for patients with lymphoma include determining if disease is present, staging, restaging, evaluating response to therapy, identifying transformation and guiding biopsy, and offering prognostic information. PET is sometimes used to diagnose infections in patients with lymphoma, as well. PET-based “risk-adapted” therapy is currently the subject of numerous ongoing investigations.
This chapter will provide a brief clinical overview of the lymphoma subtypes as well as a review of the current and possible future roles of nuclear medicine imaging in patients with lymphoma.
Epidemiology and Etiology
Hodgkin lymphoma represents approximately 10% of all lymphomas. In the United States, there were an estimated 9,050 new cases of HL and 1,150 deaths due to HL in 2015 . The number of deaths due to HL has been decreasing over the past four decades due to better treatments .
HL has bimodal age peaks in the third and seventh decades of life and a slight male predominance. The exact etiology of HL is uncertain. Factors associated with higher risk of HL vary depending on geographic location (i.e., the industrial development of a country), socioeconomic status, immune suppression, and even age. Epstein-Barr herpesvirus (EBV) has been implicated in the pathogenesis of EBV-positive HL (about 40% of HL cases ), but is less likely to have role in EBV-negative HL . Close family members of patients with HL, particularly identical twins [6, 7], are at higher risk for developing HL. One hypothesis for the etiology of HL based on the socioeconomic and genetic epidemiologic data is delayed exposure to a common (infectious) antigen in genetically susceptible individuals .
Pathology and HL Subtypes
There are two major subclasses of HL, classical and lymphocyte-predominant HL (cHL and lpHL). HL tumor is characterized by the presence of distinctive, large, malignant cells (Reed-Sternberg (RS) cells in cHL and lymphocytic and histiocytic cells in lpHL) which represent only a minority, 1–5%, of the tumor in cHL. Background infiltrates consisting of a mixture of lymphocytes, histiocytes, eosinophils, plasma cells, and fibroblasts comprise the rest of the tumor . There are four variants of cHL: nodular sclerosing, mixed cellularity, lymphocyte–rich, and lymphocyte–depleted. The variants are determined based on the morphology of the malignant cells and the composition and pattern of the background infiltrate .
Sufficient tissue is needed to make the diagnosis of HL because of the composition of the tumors, and excisional biopsy is recommended . Immunohistochemistry is a helpful adjunct to morphology for establishing the diagnosis of HL. cHL and lpHL are both monoclonal B-cell disorders arising from germinal centers, although surface antigen expression between the two subclasses is different [11, 12]. Typically, the Reed-Sternberg (RS) cell in cHL expresses CD30 and in about 80–90% of cases also expresses CD15 [13, 14]. The malignant lymphocytic and histiocytic cells in lpHL express the B-cell antigen CD20, but varying frequencies (20–35%) of CD20 expression on malignant RS cells in cHL have been reported [15, 16]. Additional immunohistochemistry stains are also useful for differentiating cHL from lpHL as well as from T-cell-rich B-cell NHL and anaplastic large cell NHL which are often in the differential diagnosis . An excellent review of the biologic classifications of HL is provided by Mani and Jaffe .
Most cHL shows clonal, somatically mutated rearrangement of V, D, and J segments of immunoglobulin heavy-chain locus in RS cells on sensitive polymerase chain reaction (PCR) techniques indicative of mature B lymphocytes . Clonal cytogenetic abnormalities with marked intraclonal variability are common in cHL [19, 20]. Abnormalities of 14q  and amplifications of PDL1 and PDL2 genes on chromosome 9  are frequent. EBV is frequently associated with lymphocyte-depleted and mixed cellularity cHL, less common in lymphocyte-rich cHL and infrequent in nodular sclerosis subtypes [22, 23]. Molecular genetics of RS cells have shown an inactivating mutation of TNFAIP3 gene which encodes negative regulator of NF-kappaB . Gene expression profiling (GEP) studies of RS cells have shown distinct expression profiles in cHL .
Clinical Presentation, Evaluation, Staging, and Prognosis
HL often presents as painless adenopathy, most commonly supradiaphragmatic in the supraclavicular and low neck lymph nodes. The pattern of nodal involvement varies depending on the histologic subtype. Thirty percent of patients also have systemic “B” symptoms (fevers, night sweats, and/or weight loss)  probably due to the production of cytokines by the malignant and background infiltrative cells .
History and physical exam, laboratory tests, and imaging are routinely performed at the initial diagnosis of HL for staging and assessing organ function prior to treatment. As will be discussed below, HL is typically FDG-avid and FDG-PET/CT is now the preferred noninvasive imaging modality for staging HL [27, 28]. According to the most recent recommendations for staging HL and NCCN guidelines, bone marrow biopsy for staging HL is no longer required if FDG-PET/CT is performed, but may be warranted for further evaluation of cytopenias if the FDG-PET/CT is negative [8, 10, 28].
Revised staging of primary nodal lymphomas: Lugano Classification
1 LN region or lymphoid structure
≥2 LN regions on same side of diaphragm
LN regions on both sides of the diaphragm or above diaphragm with splenic involvement
LN regions and noncontiguous extra-nodal sites
A – no symptoms
B – Fever (>38°C), night sweats, 10% body weight loss
E – involvement of extra-nodal site
Designation E is used for only patients with limited disease and not for advanced disease
For bulky disease, documenting the diameter is recommended and not the designation X
Patients with early-stage HL (stage I/II) are subdivided into favorable and unfavorable risk groups for overall management. The grouping definitions differ between Europe and North America. Generally, unfavorable disease is considered with larger tumor burden (either bulky mediastinal adenopathy, more nodal groups involved), older age, and “B” symptoms [31, 32]. Approximately 65% of patients with early-stage HL have unfavorable disease .
International Prognostic Score (IPS) and Indices (IPI) for HL and NHL
Hemoglobin <10.5 g/L
WBC count >15 x 109/L
Lymphocyte count <0.6 x 109/L
or <8% WBC
Serum albumin <40 g/L
Risk increasing with each increase in number of adverse factors
Elevated serum LDH
ECOG performance status ≥2
Ann Arbor clinical stage III or IV
>1 involved extra-nodal disease sites
Low intermediate: 2
High intermediate: 3
same as IPI
Very good: 0
Elevated serum LDH
Ann Arbor clinical stage III or IV
>4 involved nodal disease sites
Hemoglobin level <12.0 g/dL
Treatment and Follow-Up
The advent of multi-agent chemotherapy in the 1960s beginning with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) has led to excellent overall response rates and cure of disease in many patients [35, 36, 37, 38]. Cure rates are >90% for patients with early-stage and favorable disease, but they are in the 65–70% range for advanced disease. A complete discussion of the evolution of therapy for HL is beyond the scope of this chapter, but general management strategies are presented to place the role of imaging into the therapeutic context.
The treatment choice for early-stage HL aims to achieve cure while balancing the risks of recurrence and late toxicity (i.e., cardiac disease and secondary malignancy). For favorable early-stage HL, either combined chemotherapy and involved-field/involved-site radiation or chemotherapy alone may be appropriate [39, 40, 41, 42]. Combined modality therapy improves disease control compared to chemotherapy alone, but studies have not shown differences in overall survival [43, 44]. Shorter courses of chemotherapy may be given and smaller radiation fields applied with combined modality therapy [32, 45]. In the population with favorable early-stage HL, individual patient characteristics, such as age and specific tumor location, guide the decision-making process. For example, in young women sparing radiation to breast tissue is an important consideration.
For unfavorable early-stage HL, combined chemotherapy and radiation is favored over chemotherapy alone, especially for bulky disease . While disease-free survival is also better with combined therapy in this population, the effects on overall survival are less clear. The course of chemotherapy is typically longer (six cycles) for unfavorable, early-stage HL vs. favorable disease [10, 46].
For both early-stage favorable and unfavorable HL, adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) is the most commonly used initial chemotherapy regimen based on efficacy and toxicity profiles [8, 46, 47, 48, 49, 50]. Other initial chemotherapy options are Stanford V and bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and procarbazine (BEACOPP). BEACOPP has similar efficacy compared to ABVD, but significantly more toxicity, so it has not been recommended for early-stage disease [46, 51, 52].
Radiation field size has been reduced in recent years to avoid toxicity to normal organs. Many patients now receive involved-site or involved-nodal radiation therapy, which targets the sites of originally involved lymph nodes and considers tumor regression after chemotherapy to spare normal organs. Details are provided in the Guidelines from the International Lymphoma Radiation Oncology Group . Imaging (and increasingly FDG-PET/CT) is used to optimize these radiation fields. Another goal is lower radiation dose and dose is adjusted based on stage and tumor bulk.
For advanced HL, ABVD has been shown to be superior to MOPP and hybrid regimens [48, 49, 50] and is typically given for six cycles. More intensive regimens have been compared to ABVD. The German Hodgkin Study Group trials demonstrated better outcomes with escalated BEACOPP than with ABVD , but more acute toxicity and secondary leukemias were seen. Escalated BEACOPP is more widely used in Europe, and NCCN guidelines recommend escalated BEACOPP as an option for advanced HL with IPS >4 . It is not recommended for elderly patients with advanced HL due to acute toxicity . Randomized phase III studies comparing BEACOPP and Stanford V have not shown beneficial results. Initial results from European Organisation for Research and Treatment of Cancer (EORTC) trial number 20012 comparing eight cycles of ABVD (n = 275) to four escalated +four standard cycles of BEACOPP (n = 274) were presented in 2012 . More relapses were found in the ABVD group and more early discontinuations in the BEACOPP group, but no differences in event-free or overall survival were found between the treatment groups. The randomized Eastern Cooperative Oncology Group (ECOG) trial comparing ABVD to the Stanford V did not show a benefit of Stanford V . The role of radiation therapy to areas of bulky disease in advanced HL is also still uncertain and under investigation.
About one-third of patients with HL are refractory to or relapse after initial therapy and often receive high-dose chemotherapy and stem cell transplant . Despite high response rates posttransplant [58, 59, 60, 61], a significant number, 26–65%, of these patients relapse [57, 60, 61, 62, 63, 64]. Relapse or decreased survival posttransplant has been associated with a number of risk factors including poor performance status at transplant, chemotherapy-resistant disease, increasing number of failed chemotherapy regimens, more than minimal or bulky disease at transplant, B symptoms at relapse, and extra-nodal disease at relapse [57, 60, 61, 62, 63, 64]. Posttransplant, therapy options are limited due to patients’ decreased bone marrow reserve. Single-agent chemotherapy, local irradiation, or reduced intensity of chemotherapy followed by allogeneic stem cell transplant can be considered, but therapy is most often given with palliative intent.
Several drugs like bendamustine, lenalidomide, and everolimus have shown activity in relapsed/refractory HL and are being evaluated as second- and third-line therapies [65, 66, 67]. The antibody-drug conjugate brentuximab vedotin, which targets CD30, has been approved for treatment of refractory/relapsed HL patients who do not respond to or are not candidates for transplant . Other novel agents such as immune checkpoint inhibitors like anti-programmed death receptor-1 (PD-1) (nivolumab and pembrolizumab) monoclonal antibodies  are promising and under investigation.
lpHL has a different, more indolent natural history, and late relapses are more likely to occur compared to cHL . Non-bulky, early-stage (I/II) lpHL without B symptoms is typically treated with radiation alone. Other early and advanced stages may be treated with combinations of chemotherapy, radiation, and/or rituximab. There is no standard chemotherapy regimen for lpHL due to a lack of randomized controlled trials comparing different regimens . Because lpHL routinely expresses the CD20 antigen, rituximab used as a single agent has been studied, and very encouraging response rates have been reported [71, 72, 73]. Additional follow-up is needed to further assess the durability of the responses.
Data are limited regarding optimal follow-up of patients with HL after therapy. Generally, history, physical exam, and laboratory evaluations are performed at increasingly spaced intervals up to 5 years after completion of initial treatment. The NCCN guidelines recommend very limited imaging – CT once during the first 12 months and then as clinically needed. The use of FDG-PET/CT in follow-up is discussed further below. Additional careful follow-up is needed to monitor for late effects of treatment.
Very important considerations in treating patients with HL are the long-term side effects of external beam radiation (e.g., hypothyroidism, premature menopause, carotid and coronary artery stenosis, and secondary breast cancer) and chemotherapy (e.g., infertility, cardiomyopathy, secondary leukemia, and osteoporosis) . Increased risk of death persists for more than 25 years in patients with HL due to late-term treatment complications rather than HL itself [74, 75]. Strategies using interim PET for risk-adapted therapy may be advantageous for this purpose and for guiding dose intensification for those patients who are more likely to relapse and dose de-intensification in those responding well. This is discussed in the section on PET and risk-adapted therapy.
Epidemiology and Etiology
In 2015, the estimated number of new cases of NHL in the United States was 71,850, and NHL is the sixth most common cancer in men and the fifth most common in women . NHL resulted in about 19,790 deaths from the disease in 2015 – ranking as the ninth and sixth most common cause of cancer deaths for men and women, respectively . The incidence of NHL has been rising since the 1970s, most markedly in the elderly population. The overall increase in incidence is out of proportion to that expected due to the aging population alone, and the reasons for this are mostly unclear. Despite this, the death rate from NHL has been decreasing since 1997 due to improvements in therapy . Most cases of NHL occur in individuals greater than 60 years of age.
Alterations of the immune system, certain viruses, and environmental exposures have been implicated in the etiology of NHL, with varying degrees of evidence. For example, both immune suppression (e.g., posttransplant) and immune stimulation (e.g., Sjogren’s syndrome, rheumatoid arthritis) have been associated with increased risk of NHL [77, 78, 79]. Viral-lymphoma associations have also been suggested. Environmental exposures linked to NHL include organochlorine-based pesticides, organic solvents, and wood products.
Pathology and NHL Subtypes
NHL consists of a heterogeneous group of diseases that arise from malignant transformation of lymphoid tissues. Initial classification schemes were based primarily on morphology. Advancements in immunologic, molecular, and genetic laboratory techniques have led to several updates and revisions of classification systems for NHL [80, 81, 82]. The ability to identify cell surface markers, cytogenetic markers, and molecular markers led to the recognition that subtypes of NHL depend on the stage of maturation when malignant transformation of the lymphocyte occurs as well as the location of the “normal lymphocyte counterpart” within the lymph node.
World Health Organization Classification of NHL
Precursor B lymphoblastic lymphoma/leukemia
Precursor T-cell lymphoblastic lymphoma
Mature B-cell lymphoma
Chronic lymphocytic leukemia/small cell lymphoma
Splenic marginal zone lymphoma
Normal marginal zone lymphoma
Mantle cell lymphoma
Diffuse large B-cell lymphoma
Mediastinal (thymic) large B-cell lymphoma
Intravascular large B-cell lymphoma
Primary effusion lymphoma
Mature T-cell lymphoma
Adult T-cell lymphoma/leukemia
Mycosis fungoides (Sezary syndrome)
Primary cutaneous anaplastic large cell lymphoma
Anaplastic large cell lymphoma
Peripheral T cell lymphoma, unspecified
Angioimmunoblastic T-cell lymphoma
Extranodal NK/T cell lymphoma, nasal type
Enteropathy-type T-cell lymphoma
Hepatosplenic T-cell lymphoma
Subcutaneous panniulitis-like T cell lymphoma
Blastic NK cell lymphoma
Gene expression profiling (GEP) studies are used to diagnose and classify NHL. Based on GEP, DLBCL is classified into germinal center B-cell type and activated B-cell type [83, 84]. The activated B-cell type has been shown to have inferior 5-year survival rates compared to the germinal center B-cell type . DLBCL has chromosomal translocations, the three most common involving the oncogenes BCL-2, BCL-6, and c-MYC. Double-hit lymphomas refer to DLBCL with translocations of both c-MYC and BCL-2 or BCL-6 and carry a worse prognosis compared to other types of DLBCL . Double-expressor lymphoma refers to amplification of c-MYC and BCL-2 by mechanisms other than translocation .
Clinical Presentation, Evaluation and Staging, and Prognosis
NHL most commonly presents as painless adenopathy, similar to HL, but the rapidity of tumor growth and the exact presentation varies with histologic subtype and aggressiveness of the tumor. NHL spreads in a manner less predictable than HL (more hematogenously than by contiguous nodal spread) and is more likely to involve extra-nodal sites than HL. Systemic “B” symptoms are found in 40% of patients, more common in the aggressive than indolent NHL subtypes . Lymphomatous infiltration of the bone marrow may result in cytopenias, and the presentation of infiltration of other organs may be site specific.
A core or excisional biopsy is usually needed for diagnosis in order to provide sufficient tissue. Fine needle aspiration alone and cytology often do not provide enough tissue for morphologic, immunologic, and genetic assessment. After diagnosis, the initial work-up is similar to that of HL. History and physical exam, laboratory tests, and imaging are performed for staging and assessing organ function prior to treatment. Staging is best performed with PET for NHL subtypes that are typically FDG avid (i.e., DLBCL). Indolent NHL may sometimes have low metabolic activity, and PET for staging may be less helpful in some of these instances. Variability of FDG uptake and staging with PET in NHL are discussed further below. Bone marrow biopsy is no longer required for all patients with NHL for staging, but is reserved for those with DLBCL and a negative FDG-PET/CT in the marrow or those with low-FDG-avidity lymphomas . Laboratory testing is primarily used for prognostic scoring and to test baseline organ function prior to treatment.
Currently, NHL is also staged according to the modified Ann Arbor staging system (Table 1) [28, 88]. In the Lugano classification, four stages remain, but the subscript E is used for only when there is limited extra-nodal disease and it is not relevant for patients with advanced-stage disease. The designation “X” is replaced by largest tumor diameter for describing bulky disease, and the subdivision of patients based on constitutional symptoms is not incorporated for staging NHL (Table 1). The Lugano classification is discussed later with more detail.
The histopathologic subtype primarily determines the prognosis for patients with NHL. Within each subtype of NHL, disease-specific genetic alterations and molecular markers may provide additional information for predicting outcomes and guiding management. The International Prognostic Index (IPI) was developed in patients with aggressive NHL (Table 2) . Four risk groups were identified (low = IPI 0–1, low intermediate = IPI 2, high intermediate = IPI 3, and high = IPI 4–5) with decreasing 5-year overall survival with increasing IPI score (73%, 51%, 43%, 26%, respectively) . The original IPI was developed and validated prior to the routine use of rituximab in regimens to treat NHL. Sehn et al.  retrospectively evaluated the use of the IPI in 365 patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). Using the original IPI groupings, only two (not four) risk groups were identified. The revised IPI redistributed the risk groups (very good = IPI 0, good = IPI 1–2, poor IPI 3–5), and this model was felt to better predict outcome. In the rituximab era, the risk group with 4-year survival <50% was no longer identified .
Additional variations of the IPI have been developed, including age- and stage-adjusted IPIs to account for the variability of prognoses within these groups [89, 91]. The enhanced IPI (NCCN-IPI) was reported recently in a study of 1,650 patients to discriminate low- and high-risk subgroups better than IPI, a finding validated in another independent cohort of 1,138 patients . The usefulness of the IPI also has been shown to provide prognostic information at the time of relapse [93, 94, 95, 96].
There are two versions of the IPI for patients with indolent follicular NHL (FLIPI 1 and 2). Using the first FLIPI version, overall survival decreases with increasing FLIPI score based on three risk groups (low, intermediate, and high) and provides prognostic information for this population, even in the setting of rituximab [97, 98]. Validation of FLIPI 2 is ongoing.
Treatment and Follow-Up
As with the natural history and prognosis of NHL, treatment varies and depends on the specific NHL subtype. Recommendations for detailed management strategies are provided by a panel of experts in the NCCN guidelines . Excellent review articles are available for specific questions and agents for the treatment of NHL, including new biologic agents and treatment strategies [100, 101, 102, 103, 104, 105]. We will review overall management strategies for the most common NHLs – DLBCL and follicular NHL. These are also probably the most commonly encountered by the nuclear medicine physician or radiologist. Discussion of treatment for the other subtypes is beyond the scope of this chapter and can be found elsewhere [99, 106].
Indolent NHL is generally considered incurable at present. Patients respond to therapy, but may have multiple relapses and long disease-free or progression-free periods. A major question for those with indolent NHL is when to initiate therapy. Several studies have shown that “wait and watch” is a valid strategy even in the rituximab era outside of clinical trials in patients with advanced-stage low-tumor burden follicular lymphoma [107, 108].
General indications for treatment of indolent NHL are symptoms, organ compromise, rapid or steady progression of tumor, bulky disease, cytopenias due to lymphoma, and patient preference or eligibility for a clinical trial . The treatment plan and aggressiveness of the regimen used are usually tailored for the patient’s disease and clinical status. Common regimens include purine analogs, alkylators, anthracyclines, and rituximab alone or in combination with chemotherapy. Selected patients with bulky early-stage disease may be treated with radiotherapy alone.
Sousou and Friedberg nicely reviewed the pivotal studies that investigated the role of rituximab in patients with indolent lymphoma . Treatment with rituximab alone [110, 111, 112] and with chemotherapy [113, 114, 115, 116] has improved overall response rates and PFS for patients with indolent NHL in both the front line and maintenance settings . There is a suggestion toward improved overall survival [118, 119], which has been confirmed in long-term follow-up data . Patients who respond to first-line therapy can be treated with maintenance rituximab up to 2 years . Consolidation with radioimmunoconjugates in patients initially treated with chemotherapy alone has been shown to improve the quality of remission but not better than initial chemoimmunotherapy alone [121, 122, 123]. Areas of continued study for rituximab are use with immune stimulators to improve efficacy, optimal schedule for maintenance dosing, and resistance mechanisms. Other monoclonal antibodies to CD20 are also being developed and investigated .
In the relapsed setting, indolent NHL may be treated in a similar manner to initially untreated disease. Overall response rates to rituximab in the relapse setting range from 40% to 60% with complete responses in 10–20% and median progression-free survival (PFS) of 8–24 months [112, 125, 126]. Radioimmunotherapy is more active and produces better results than unlabeled antibody alone, and its use in relapsed (as well as the front line) indolent NHL is discussed in a separate chapter [121, 122, 123, 127, 128]. Autologous and allogeneic transplants have been performed safely and with antitumor activity prolonging the overall survival and progression-free survival [129, 130]. If there is a role for transplant in indolent lymphoma, the optimal role is still being defined.
For aggressive B-cell NHL, systemic chemotherapy is the mainstay of treatment. Diffuse large B-cell NHL is the most common aggressive NHL and is discussed as an example. The present regimen of choice is R-CHOP [131, 132, 133]. For non-bulky early-stage disease, the NCCN guidelines recommend three cycles of R-CHOP with IFRT or six cycles of R-CHOP with or without IFRT . Higher doses of IFRT (30–40 Gy) are added to six cycles of chemotherapy for early-stage, bulky disease. The preference at major centers is to treat patients with advanced disease on a clinical trial; otherwise, a full course of chemotherapy is recommended [99, 131]. For germinal center B-cell type DLBCL patients treated outside the setting of a clinical trial, the choice of treatment is R-CHOP-21 (R-CHOP given every 21 days). Two randomized phase III trials have shown that dose-dense R-CHOP-14 does not improve the outcome compared to R-CHOP-21 [134, 135] . Clinical trials of R-CHOP with novel agents like lenalidomide, ibrutinib, and bortezomib are available for patients with advanced activated B-cell-type DLBCL [136, 137, 138]. For patients with double-hit DLBCL, dose-adjusted EPOCH-R has been shown to be associated with better outcome than R-CHOP [139, 140]. The NCCN recommends several alternate first-line regimens for frail patients .
The role of high-dose therapy and transplant for initial therapy of aggressive NHL is controversial and the subject of clinical trials. Currently, autologous hematopoietic cell transplantation (HCT) is not recommended after initial treatment of DLBCL as there is no survival advantage with HCT . FDG-PET/CT is being used as a prognostic indicator in several of these risk-adapted therapy trials, and these studies are discussed in the section on risk-adapted therapy. In the relapsed setting, there are several salvage chemotherapy regimens that may be used with the ultimate goal of transplant in those patients who respond.
T-cell NHL accounts for ~15% of all lymphomas. Most T-cell lymphomas are clinically aggressive, and with a few exceptions (anaplastic large cell, early-stage T-/NK cell, nasal), most are incurable. CHOP and CHOP-based therapy may be used for initial treatment in these settings with or without radiotherapy [142, 143, 144]. Certain subtypes of T-cell NHL can be treated with consolidation radiation or HCT . The optimal regimen for treatment of adult T-cell leukemia/lymphoma is yet to be established. Other approaches have been investigated for T-cell NHL subtypes including investigations of biologic agents (bevacizumab  and histone deacetylase inhibitors ) and agents against other lymphocyte surface antigens (alemtuzumab , mogamulizumab , brentuximab ).
Follow-up for patients with NHL also depends on the subtype of NHL, treatment intent, and the patient’s clinical symptoms. For those treated with curative intent, history and physical exam, laboratory testing, and imaging occur with decreasing frequency over the first 5 years and then annually. Patients must be monitored for late complications of therapy, which are similar to those discussed for HL.
Nuclear Medicine Imaging for Lymphoma
Nuclear medicine imaging has had a role in the evaluation of patients with lymphoma since the 1970s . Gallium-67 imaging preceded FDG-PET/CT as the functional imaging technique for staging, monitoring response to therapy, and providing prognostic information [151, 152, 153, 154, 155, 156, 157]. A negative gallium-67 scan favored a better outcome after treatment and as soon as after one cycle of chemotherapy in both HL and NHL [153, 154, 155, 156, 157]. Other agents were also evaluated, for example, indium-111 bleomycin, but they were not shown to be more efficacious than gallium-67 [158, 159].
Today, gallium scanning has been replaced with FDG-PET/CT imaging, which offers higher-resolution images; higher sensitivity for disease detection, particularly for lower-grade lymphomas; lower radiation doses; and a shorter time from injection until imaging is performed [159, 160, 161, 162, 163, 164]. Bone scanning has also been used for detection of lymphomatous involvement in bone; however, these typically marrow-based lesions may be falsely negative on bone scan. In the PET era, bone scanning is considered if patients present with bone pain and a PET scan is not available . FDG-PET/CT is now well integrated into management strategies for lymphoma. The current roles of PET (disease detection, staging, and posttreatment assessment) are reviewed. Numerous ongoing clinical trials investigating the role of interim PET, obtained after one to four cycles of chemotherapy, for risk-adapted therapy will be discussed.
FDG-PET for Detecting and Histologic Grading of Lymphoma
Most lymphomas accumulate FDG . Weiler-Sagie et al.  readdressed this issue in a large retrospective study of 766 patients with newly diagnosed lymphoma referred for initial staging with FDG-PET/CT. FDG-avid disease was found in all patients with HL, 94% with aggressive NHL and 83% with indolent NHL. The histologic subtypes of lymphoma less likely to be FDG-avid were small lymphocytic lymphoma (% FDG avid – 83%), enteropathy-type T-cell lymphoma (67%), extra-nodal marginal zone lymphoma (67%), MALT marginal zone lymphoma (54%), lymphomatoid papulosis (50%), and primary cutaneous anaplastic large T-cell lymphoma (40%) .
To some extent, the location of lymphomatous involvement may also hinder its detection regardless of histopathologic subtype. The cutaneous location accounted for one-third of the 48 non-FDG-avid cases in Weiler-Sagie et al.’s study , including two with DLBCL. The other most common locations of non-FDG-avid disease were bowel, bone marrow, effusions, and mucosal surfaces . Clearly tumor burden has an effect, and low tumor burden can be falsely negative.
Weiler-Sagie et al. did not address the degree of FDG uptake in the histologic subtypes of lymphoma, but this has been done previously . Broadly speaking, low-grade lymphomas take up less FDG than high-grade lymphomas [166, 167, 168]. Standardized uptake values (SUVs – a semiquantitative measure of tumor metabolism) of greater than 10 had a high likelihood of being aggressive and excluded low-grade lymphoma with a specificity of 81% in one study of patients with non-Hodgkin lymphoma . Despite this, there is substantial overlap of FDG uptake between lymphoma grades with some low-grade tumors exhibiting high levels of FDG uptake. The level of FDG uptake likely lies along a continuum based on the histologic grade of the lymphoma, but in an individual patient, the level of FDG uptake is probably not an adequate single surrogate marker for histologic grading of lymphoma.
Bodet-Milin et al.  used PET/CT to prospectively guide biopsy in 38 patients with indolent NHL (n = 23 follicular, n = 10 CLL, n = 2 Waldenstrom macroglobulinemia, n = 3 marginal zone NHL) and clinical suspicion for transformation. Biopsy was obtained at the most accessible site with the highest SUVmax, and 17 patients had histologic transformation on biopsy. The median SUVmax and gradient SUVmax (highest SUVmax-lowest SUVmax) were higher for those with histologic transformation. Using receiver operator curve analysis, an SUVmax threshold of 14 was optimal for identifying transformation (sensitivity/PPV ~ 94%, specificity/NPV ~95%) . As expected, sensitivity or specificity could be improved one way or the other with higher and lower thresholds. Bodet-Milin’s study differed from Bruzzi’s in several regards; all patients had a clinical suspicion of transformation, and higher threshold values for transformation likely decreased the false-positive rate. They suggest that a higher threshold may be reasonable for patients with follicular versus chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), as CLL/SLL typically has less FDG uptake at baseline . These data together suggest that PET may be useful for detecting transformation, but tissue confirmation is still required for confirmation at the present time. It should be noted that SUV in all nonfat tissues can be elevated in obese patients; thus, the SUV of 10 is a rough guideline, only.
FDG-PET for Initial Staging of Lymphoma
The Lugano classification recommends FDG-PET/CT as the imaging test of choice for staging all FDG-avid nodal lymphomas. Contrast-enhanced CT is recommended for the staging of all non-FDG-avid lymphomas. The modified Ann Arbor staging is still used in the Lugano classification  (Table 1). The suffixes A and B for constitutional symptoms are recommended only for HL. The designation E is used for only patients with limited disease and not for advanced disease. For bulky disease, documenting the diameter is recommended and not the designation X (Table 1).
Although biopsy is the gold standard to detect lymphomatous involvement in the bone marrow, bone marrow biopsy and FDG-PET have been reported to be approximately 80% concordant [173, 176, 177]. The Lugano classification does not recommend bone marrow biopsy in HL if FDG-PET/CT is performed . This recommendation is based on several studies showing that FDG-PET/CT is sensitive for detecting involvement of bone marrow in HL [178, 179]. Sampling error on biopsy may result in a “false-positive” PET study, which is actually true positive (Fig. 3). El-Galaly et al. showed that only one-third of 454 HL patients with focal skeletal lesions on FDG-PET/CT were positive on bone marrow biopsy .
When evaluating an abnormal focus of increased FDG uptake in the bone, it is important to note that the concurrent CT scan may appear normal up to 50% of the time  and the context and entire distribution of uptake must be considered. In the lymphoma population in the study by Nakamoto et al., none of the marrow lesions were seen on CT, but the population was small . FDG-PET is more likely to detect bone marrow disease when greater than 30% of the marrow is involved. False-negative FDG-PET scans for bone marrow disease (PET negative, biopsy positive) occur if less bone marrow is involved, in lower-grade histologies, or if the primary nodal disease is not FDG-avid. Misinterpretation of diffuse FDG uptake in the marrow due to concurrent systemic illness or recent administration of hematopoietic growth factors can potentially lead to false-positive FDG-PET scans. This can be avoided by a carefully elicited clinical history.
FDG-PET/CT Versus PET Alone
A majority of studies investigating the use of metabolic imaging in lymphoma have evaluated FDG-PET alone. Tatsumi et al.  reported that combined FDG-PET/CT imaging may be better than either modality alone. In 53 patients with lymphoma, 48 of 1,537 findings were discrepant between PET and CT; 40 were correct PET findings, 5 were correct CT findings, and 3 remained uncertain. Nine patients were only staged correctly with PET/CT versus CT alone . Allen-Auerbach et al.  found that PET/CT was more accurate than PET alone for the detection of lymphoma (94% versus 84%, respectively). PET/CT improves lesion localization, allows detection of lesions that might be missed by either modality alone, and provides more reliable tumor measurements. Though contrast-enhanced CT with PET can help in improving the sensitivity of detecting nodes and other clinically relevant findings, the impact on patient management is very minimal [193, 194, 195]. However, the Lugano classification still recommends contrast-enhanced CT for accurate nodal assessment in the setting of clinical trials, radiotherapy planning, and vascular thrombosis .
Post-Therapy Response Assessment by FDG-PET and PET/CT
Despite its improved prognostic implications, a negative post-therapy PET scan does not exclude the presence of residual microscopic disease that falls below the resolution of the PET scanner [175, 197, 198, 199, 200, 201]. The resolution of modern PET scanners falls between 0.5 and 1.0 cm  which converts to about 108–109 tumor cells . Patients who are PET negative with a residual mass are more likely to recur than those who are PET negative without residual mass [175, 197, 198, 199, 200, 201].
The optimal time to obtain a post-therapy PET is a frequent question of referring oncologists, but the answer is not completely resolved. A minimum of 10 days post-chemotherapy has been recommended to avoid false-negative scans due to the early treatment effect of “stunning” . Longer and more variable times post-external beam radiation have been suggested , and optimal interval times post-radioimmunotherapy are beginning to be investigated and discussed in the chapter on radioimmunotherapy [206, 207].
Integration of FDG-PET and PET/CT into Tumor Response Criteria
FDG-PET/CT is now an integral component of assessing lymphoma response to therapy. Historically, the first major criteria for assessment of treatment response in lymphoma were proposed by the International Working Group (IWG) in 1999. Five categories of response were defined based on CT including the category of “complete remission – unconfirmed” for cases with post-therapy residual masses. These IWG criteria  were revised in 2007 to include a post-therapy assessment by FDG-PET  based on the numerous studies showing the predictive value of the post-therapy FDG-PET scan and a retrospective, but pivotal, study in 54 patients with aggressive NHL . In this study, the integrated PET and IWG response criteria more accurately classified lymphoma response by identifying a subset of partial responders by IWG criteria who had a complete metabolic response by FDG-PET (i.e., PET negative) and a more favorable prognosis . The integrated criteria were subsequently found to be applicable to indolent NHL and HL [211, 212]. At the time of this writing, the most current version of the criteria is the Lugano classification .
The Lugano classification was developed to improve both the staging and response criteria for HL and NHL following a workshop held at the 11th International Conference on Malignant Lymphoma in Lugano, Switzerland, in June 2011 and a subsequent workshop at the 12th International Conference on Malignant Lymphoma in 2013 .
Deauville 5-point scale
Uptake ≤ mediastinal blood pool
Uptake > mediastinal blood pool but ≤ liver
Uptake moderate > liver
Uptake markedly > liver and/or new lesions
New areas of uptake unlikely to be related to lymphoma
Lugano Criteria for Response Assessment in Lymphoma
Score 1,2,3 with or without residual mass in nodes or extra-nodal sites
Complete disappearance of all sites of disease or decrease in size of nodes to ≤1.5 cm in LDi
Score 4 or 5 with decreased uptake compared to baseline and residual masses of any size
≥50% decrease in PPD (single lesion) or SPD of six measurable target nodes and/or extra-nodal sites (multiple lesions); decrease in spleen size >50% in length beyond normal
No response/ stable disease
Score 4 or 5 with no obvious change in FDG uptake compared to baseline
<50% decrease in PPD (single lesion) or SPD of six measurable target nodes and/or extra-nodal sites (multiple lesions) and no criteria for progressive disease
Score 4 or 5 with increase in intensity of FDG uptake compared to baseline or new foci of FDG uptake compatible with lymphoma
New or increased adenopathy (nodes 1.5 cm > LDi, PPD ≥ 50% from nadir, LDi or SDi increase from nadir by 0.5 cm for lesions ≤2cm and by >1.0 cm for lesions > 2.0 cm), increase in splenic length by >50% of its prior increase from baseline, or by at least 2cm from baseline if no prior splenomegaly, new or recurrent splenomegaly, new nodal or extranodal sites or increase of preexisting nonmeasurable lesions
Concurrent with the publication of the Lugano classification, the consensus report from the imaging subcommittee of the International Harmonization Project in Lymphoma on the acquisition and interpretation of PET scans that accompanied the revised IWC  in 2007 was also updated . The general recommendations and major changes from 2007 are summarized in Table 5.
Multiple consensus reports using PET for response assessment (interim and post-therapy) in lymphoma and other tumors stress the importance of obtaining high-quality, standardized PET and CT scans on dedicated PET systems. Detailed discussions on obtaining such scans are found in reports by the National Cancer Institute  and the Netherlands multicenter trial group  and reviewed in the revised IWC  and PET Response Criteria in Solid Tumors (PERCIST) .
The use of FDG-PET for routinely monitoring the response of low-grade follicular and other indolent lymphomas is debatable, but given that the method is more sensitive and specific than CT, it is gaining greater acceptance in clinical practice. Assessments of lower-grade/indolent lymphomas that are FDG avid with PET/CT are now included in the new Lugano classification [27, 28].
Interim PET and Risk-Adapted Therapy
Theory and Biologic Basis
Chemotherapy of tumors begins to affect tumor metabolism soon after it is started. In 1993, PET was used sequentially to assess breast cancer response to chemohormonotherapy, and decreases in the amount of FDG uptake in responding tumors were seen by 8 days into treatment . The clear predictive value of PET in the post-therapy setting for patients with lymphoma has led investigators to evaluate its usefulness earlier during the course of chemotherapy, and numerous studies have upheld PET’s prognostic value in the interim therapy setting [225, 226, 227, 228, 229, 230, 231]. Event-free survival (EFS) is consistently lower in patients with positive interim PET scans (0–46%) compared to those with negative interim scans (62–98%), despite variability in the study designs (prospective vs. retrospective, chemotherapy cycles, qualitative vs. quantitative PET assessments), tumor histologies, and treatments employed. This body of work, including a landmark study by Gallamini et al.  (discussed below), is the premise for risk-adapted therapy for patients with lymphoma.
Importantly, Gallamini et al.  showed that in 190 patients with advanced HL, the results of early interim PET after two cycles of ABVD chemotherapy were more predictive than the widely used and validated IPS. As previously discussed, the IPS for HL and IPI for NHL are both currently used to guide management decisions. Both indices are based solely on pretreatment parameters and do not consider the inherent “chemosensitivity” of the tumor or the rate of tumor kill which are both related to outcome, but PET can assess both of these factors .
The conceptual framework for PET providing an early readout on “chemosensitivity” is nicely discussed by Kasamon, Jones, and Wahl, and two underlying points are summarized [203, 232]. First, chemotherapy is expected to kill the same percentage of cells during each cycle (first-order kinetics) . For example, 11 cycles of chemotherapy are needed for cure with 1010–1011 cancer cells. Second, due to the lower limit of resolution for current scanners, PET can only detect the initial logs of cell kill. A negative scan after therapy either means cure or residual microscopic disease. A true-negative interim therapy (or soon post-therapy) scan implies that the rate of kill is fast enough to achieve cure by the end of therapy, whereas a positive interim therapy scan does not [203, 232].
The logical question follows, “Can the prognostic information from an interim therapy PET scan be used to improve therapeutic strategies for patients based on their individual risk, hence risk-adapted therapy?” And this can be considered in two ways. First, should therapy be intensified to improve the chance of cure in a patient with a positive interim PET scan as cure is unlikely with the initial therapy? On the other hand, is it safe to omit or decrease therapy in a patient with a negative interim scan? As alluded to in the section above on treatment for early-stage HL, this second option is particularly attractive to reduce the long-term toxicities from therapy in this otherwise curable population.
To date, there are a small number of published trials, but an even larger number of ongoing trials that are investigating these questions. These trials are reviewed and limitations of the use of interim therapy PET for risk-adapted therapy discussed. Until the results of these trials are available and more mature, interim PET scanning and risk-adapted therapy should be performed in the clinical trial setting .
Clinical Trials of Risk-Adapted Therapy for Aggressive NHL
A negative interim PET/CT performed after two to three cycles of chemotherapy has been shown to predict a favorable outcome. Kasamon et al.  published a phase II study in 59 patients with aggressive NHL, hypothesizing that suboptimal response on interim PET (PET positive) was a sign of chemoresistance and that intensifying therapy in this group of patients would improve their outcome. After two to three cycles, R-CHOP chemotherapy was continued for a negative interim PET (tumor uptake ≤ mediastinal blood pool) or intensified to high-dose therapy and autologous stem cell transplant (ASCT) for a positive interim scan (tumor uptake > mediastinal blood pool). On an intent-to-treat basis and at median follow-up time of 34 months, 2-year event-free survival (EFS) was 67% (95% CI 53–86%) in patients with positive interim PET versus 89% (95% confidence interval 77–100%) for negative interim PET. The IPI was not associated with the interim PET result. The outcome of the PET-positive group compared very favorably to historical controls where <20% PFS was expected174. In another study of 103 patients with untreated DLBCL who were treated with CHOP with or without rituximab, a negative PET after four cycles of treatment was associated with 5-year EFS of 80% compared to 36% for patient with positive PET .
The predictive value of interim PET in DLBCL is, however, less clear as few studies have shown that interim PET can be falsely positive and associated with favorable outcome [236, 237]. Moskowitz et al.  performed a phase II study of risk-adapted therapy in advanced DLBCL, but with a slightly different strategy. The treatment scheme was dose-dense R-CHOP followed by PET after four cycles. PET-negative patients received ifosfamide, carboplatin, etoposide (ICE) alone for three more cycles. All PET-positive patients underwent biopsy, contrary to Kasamon’s study, and received two cycles of ICE. If the biopsy was negative, an additional cycle of ICE was given, but if positive, therapy was intensified to R-ICE, high-dose therapy, and ASCT. Interim PET scans were positive in 38 of 97 patients. Five of these 38 patients had a positive biopsy for tumor and proceeded to ASCT. The remaining biopsies showed inflammation. At a median of 44 months of follow-up, EFS was not significantly different between interim PET-negative patients and PET-positive/biopsy-negative patients. Three of the five patients who underwent ASCT were alive and progression free at the time of publication.
Possible explanations offered for the high “false-positive” rate on PET were dose-dense initial therapy, increased inflammation due to greater use of rituximab than in prior studies, interim scan occurring relatively soon, a median of 12 days after last therapy (although longer than minimal recommendation of 10 days [220, 221]), the reader threshold for determining “positivity” of a scan, and consolidation to ICE for all patients . The authors concluded and recommended that biopsy be performed to confirm interim-positive PET scan findings prior to treatment intensification to ASCT . It is also possible that false-negative biopsies occurred. It should be noted there is little data on the predictive value of biopsy in this setting. In another study of 88 patients with newly diagnosed DLBCL treated with R-CHOP, there was no significant difference in the 2-year PFS between patients with negative and positive interim PET. The end-of-therapy PET was highly predictive of the 2-year PFS .
Clinical trials in aggressive NHL have primarily focused on intensification of therapy if the interim scan is positive and exploring findings of the previous risk-adapted trials. The results of the ECOG 3404 study were recently published . This study evaluated interim PET response-based strategy of switching patients to R-ICE chemotherapy after three cycles of R-CHOP. The interim PET was scored as positive or negative by central review. A 2-year PFS of ≥45% was the target response in the interim PET-positive group. The scans were interpreted using customized binary criteria (ECOG criteria). The study enrolled 74 patients and only 16% of patients had a positive interim PET. A rereview of the interim scans by an expert panel was performed due to the low number of the positive scans. Nearly 30% of the interpretations were discrepant among the readers highlighting the need for more accurate scoring system or possibly precise quantitation of the images. The 2-year PFS was 76% in the interim PET-negative group and 42% in the interim PET-positive group treated with R-ICE. The authors concluded that the poor outcome of patients with interim PET positivity despite intensification of therapy indicates innate resistance to treatment and that until further evidence is available, treatment modification in DLBCL patients based on early PET should remain restricted to clinical trials .
The current NCCN guidelines also state that treatment modification of DLBCL patients should not be guided by interim PET scan results. Any modifications should be performed only after conforming real positivity on repeat biopsy of residual masses . The demonstration of true benefit of therapy intensification for those with a positive interim PET scan is limited by comparison to historical controls and the lack of randomization to standard versus experimental therapy in the above phase II trials. An ongoing study in Germany, Positron Emission Tomography Guided Therapy for Aggressive Non-Hodgkin’s Lymphomas (PETAL), attempts to address this . In this study, patients with positive PET scans are randomized to either six additional cycles of R-CHOP or a more intense Burkitt’s lymphoma regimen. For those randomized to R-CHOP, two additional cycles are given (total eight cycles) compared to those who have a negative interim PET scan (total six cycles). The interim results of this trial have shown relapses more often in patient with positive interim PET than patients with negative interim PET . Recruitment into this trial is ongoing, and the results should provide further insight into the usefulness of PET in the interim setting for aggressive NHL.
Clinical Trials of Risk-Adapted Therapy for Hodgkin Lymphoma
Risk-adapted therapy is also a major focus of research trials for patients with HL. For those with early, unfavorable, or advanced disease, the approach is generally similar to NHL, intensification of therapy based on a positive interim scan. For those with early-stage disease, therapy de-intensification after a negative interim PET is undergoing ongoing evaluation in attempt to reduce the risk of late-term complications from potentially excessive therapy.
There are several trials evaluating risk-adapted strategies in early-stage favorable HL. The interim results of the EORTC/LYSA/FIL H10 trial evaluating the non-inferiority of omitting radiotherapy in early interim PET-negative patients with early HL have been published . A total of 1,137 patients were recruited in the study and assigned to standard and experimental arms. Nine hundred patients (favorable = 381 and unfavorable = 519) had interim PET-negative disease. Interim futility analysis showed that in both favorable and unfavorable groups, the experimental arm (chemotherapy alone) had a greater number of relapses or early progression compared to the standard arm (standard chemotherapy and radiotherapy). Based on these results, the independent data monitoring committee recommended closure of accrual to the PET-negative experimental arm. The UK RAPID trial was a phase III trial which also evaluated the non-inferiority of no further treatment versus involved-field radiotherapy in patients with a negative interim PET . Of the 571 patients who underwent PET scanning in the study, 74.6% patients had negative PET. The 3-year PFS and OS in the no further treatment group (n = 211) were 90.8% and 99.0%, respectively, compared to 94.6% and 97.1%, respectively, in the radiotherapy group (n = 209). Overall, the study concluded that the strategy of no further treatment was not non-inferior to consolidation radiotherapy although the prognosis was very good in both arms with or without radiotherapy. That said, it appears that the possible benefits of radiotherapy were quite modest relative to the number of patients that needed to receive the treatment.
Dann et al.  performed a prospective study of risk-adapted BEACOPP therapy in 108 patients with intermediate- and high-risk HL. Treatment was adapted based on pretreatment risk factors (standard BEACOPP for intermediate-risk disease or escalated BEACOPP for high-risk (IPS ≥ 3) disease) and then escalated or de-escalated based on interim functional imaging with gallium-67 or PET after two cycles. With this schema, 5-year EFS and OS were not different between the intermediate- and high-risk groups at a median of 47 months of follow-up. In the high-risk group (n = 39), 31 (79%) had therapy de-escalated for negative interim scintigraphy, and the negative predictive value of interim PET was 93%. The authors suggested that it may be feasible to de-escalate therapy in a high-risk group based on negative interim PET. Only 4 of 19 patients (21%) with a positive interim PET scan had progressed at last follow-up (median 47 months). Several additional ongoing trials of risk-adapted therapy for advanced-stage HL, mostly therapy intensification with positive interim PET, are in references [243, 244, 245].
The interim data of the response adapted therapy in advanced HL (RATHL) have been recently published . The results of the study indicate good agreement between readers while using the 5-point scale for interim PET assessment. The final results on the role of interim PET in treatment adaptation are awaited. In the yet-to-be-published GITIL/FIL HD0607 trial, the role of early intensification of therapy in advanced-stage HL patients with positive interim PET has been evaluated . Patients with positive PET after two cycles of ABVD were treated with BEACOPP escalated and BEACOPP baseline (4 + 4) without or with rituximab. On the other hand, patients with negative interim PET received four cycles of ABVD with or without RT. Of the 446 patients with interim PET, 20% had positive scans. Response to treatment was assessed in a cohort of 263 patients (15% with positive interim PET and 84% with negative interim PET). Complete response to treatment was seen in 73% of PET-positive patients and 95.5% of PET-negative patients . The results of many other trials are awaited.
Interpretation of Interim Therapy PET Scans
Most risk-adapted therapy trials have employed qualitative analyses (i.e., visual scales) for interpreting interim PET scans as positive or negative. Several have been used (Juweid et al. , ECOG  and London criteria ), and these scales have evolved over the years. As indicated in the section above, the Deauville criteria are currently used in the interim setting (give Lugano reference).
Cases of FDG uptake in tumor much less or much greater than background are clear-cut as negative or positive; however, FDG uptake in tumor occurs along a continuum. Most of the difficulty arises in the concept of “minimal residual uptake” (MRU) and the optimal definition of “background” (and thus the cutoff point for a positive vs. negative scan) in the interim setting. MRU was first defined in 2000 as low-grade uptake on posttreatment PET within an area of previous disease, reported as likely inflammation but where a small volume of malignancy cannot be excluded . The definition of MRU has been adapted slightly over recent years by different investigators, hence the variable criteria and interpretation of interim PET scans for studies of patients with NHL and HL.
In a study of aggressive NHL, Kasamon et al.  found that 56% of patients had a positive interim PET scan using mediastinal blood pool as a comparator. In the follow-up ECOG study (E3404), a centralized PET review by a single reader took place, and the rate of positive interim PET scans was lower than expected. As a result, evaluation of the reproducibility of interim PET interpretation took place . Three expert PET readers scored baseline and interim PET scans from 38 patients on E3404 using the ECOG and London criteria without additional training. Only moderate reproducibility among the experts was found for interpreting the interim scans (k = 0.44 for ECOG criteria and k = 0.50 for London criteria).
The sources of disagreement were lesions in the para-aortic region, bone, and spleen . These sites of disagreement are not completely unexpected as the spleen and bone marrow can have considerably heterogeneous uptake post-therapy due to treatment effects.
On the other hand, Barrington et al. have reported very good agreement among four centers in Europe for interpretation of interim PET using the London criteria (RATHL trial) . The interim PET scans were read independently by the participating centers and then in consensus. The kappa values showed very good agreement for negative (uptake less than or equal to the liver) vs. positive (uptake moderate or markedly increased versus the liver) scans for both the independent (k = 0.85, 95% CI 0.74–0.96) and consensus readings (k = 0.90, 0.79–1.00) . Agreement was slightly less for independent reads when the category of “uptake greater than mediastinal blood pool but less than liver” was considered separately (from negative or positive). The updated results of the RATHL study made similar conclusions. There was good agreement in the interpretation of the interim PET scans using the Deauville 5-point scale (5-PS) among experts (k = 0.84, 0.76–91) and between experts and local readers (k = 0.77, 0.68–0.86) .
Some uncertainty does remain in the optimal cutoff for altering therapy based on interim PET. Mikhaeel et al. showed that for patients with early-stage NHL, the MRU survival curve lies closer to those who have a negative interim PET, but in late-stage disease, the MRU curve lies closer to the PET-positive curve . The significance may vary based on a combination of factors, including clinical stage, lymphoma subtype, and benefits and risks of the impending therapeutic decision. The use of semiquantitative parameters like the standardized uptake value (SUV) may be helpful in the interim setting to help reduce the variability if PET is performed using standardized methods.
Lin et al.  found that in patients with DLBCL, a decline in maximum SUV of >65.7% after two cycles of therapy better predicted outcomes versus visual assessment by reducing the number of false-positive scans. These results did not hold, however, in a subsequent study where PET was performed after four cycles of therapy . Optimal methods for assessing PET may be also be dependent on timing of the scan.
Standardized response criteria for interim PET scanning and the results of the many ongoing trials will hopefully provide the necessary data to determine if risk-adapted therapy is possible and beneficial for individual patients. At the present time, most experts agree that changes in therapy based on interim therapy PET (except for progressive disease) should currently be kept in the context of clinical trials. The current NCCN guidelines recommend interim PET scan assessment with Deauville criteria in both early-stage favorable and advanced-stage disease . In a large retrospective multicenter study published recently, the reproducibility of Deauville 5-PS for interpretation of interim PET was assessed . The study included 260 patients with early-stage unfavorable or advanced-stage HL treated with chemotherapy with or without consolidation radiotherapy. The interim PET scans were positive as per Deauville criteria in 17.3% patients. A three-year PFS was 28% for interim PET-positive patients compared to 95% for PET-negative patients. Interim PET had sensitivity and specificity of 73% and 94% for predicting outcome. There was strong concordance among reviewers while using the Deauville criteria (Cohen’s kappa 0.69–0.84) .
Full quantitation of images holds the potential to reduce variability among readers, but will require further study.
Surveillance PET for Lymphoma
In HL and aggressive NHL, early detection of relapse is desirable in order to initiate treatment when tumor burden is low. This may increase the chance of successful disease eradication, which ultimately may lead to better outcomes. Several studies have shown that recurrence of lymphoma is often diagnosed by the presence of clinical symptoms before detection or confirmation by imaging [254, 255, 256]. PET offers a potential benefit over anatomic imaging for earlier disease detection, but this must be balanced with considerations of radiation exposure to the patient and cost from the increased number of scans obtained during surveillance.
The current literature on the use of PET for follow-up of patients with lymphoma is limited. However, it does confirm the ability of PET to detect relapse before the patient becomes symptomatic and before anatomic imaging becomes positive, by up to 9 months in one study . PET is also useful for detecting relapse in the setting of a persistent, unchanging residual mass on CT in the follow-up period . For patients who achieve a complete remission after therapy, the negative predictive value of PET for excluding relapse in the follow-up period is high (99–100%) [257, 258, 259].
The major limitation of surveillance PET has been a high false-positive rate (low positive predictive value, 11–53%) in several studies [257, 258, 259]. This is particularly true in the pediatric population of patients where cure rates are high and the incidence of recurrent disease is low. In the study by Rhodes et al. , false-positive results occurred due to reactive neck lymph nodes. Another contributing factor to these high false-positive rates was that PET alone was used, and conditions such as rebound thymic hyperplasia or brown fat were recorded as positive for disease recurrence. This is much less likely to occur in the current era of PET/CT and as we have gained knowledge in interpretation of post-therapy PET in patients with lymphoma.
Zinzani et al.  prospectively performed follow-up PET scans (every 6 months for 2 years and then yearly) in 421 adult patients with lymphoma who achieved a complete response by PET after therapy (160 with HL, 183 with aggressive NHL, 78 with indolent NHL). For HL and aggressive NHL, the number of true-positive scans decreased and true-negative scans increased with time. The incidence of relapse was stable over time for those with indolent NHL, as might be expected. Compared to the prior studies in pediatrics, the false-positive scan rate was low (~1% of 1,789 scans). However, eight percent of patients had inconclusive-positive PET scans, two-thirds with concurrent negative CT scans, and biopsy was important to confirm disease presence in these patients. Most patients with inconclusive negative scans did not relapse .
The early studies did show that there may be a subgroup of patients for whom PET might be useful for surveillance. Rhodes et al.  suggested that those children with residual masses or unchanging abnormal CT scans might benefit the most from surveillance PET scanning. Zinzani et al.  also found that PET positivity was more common in groups with a higher risk of recurrence by prognostic factors for all lymphoma types. These findings are further supported by a more recent study by Petrausch et al. who found that the usefulness of PET for surveillance may be related to risk factors at the time of scanning [261, 262].
Petrausch et al.  evaluated 134 patients with HL in remission after first-line therapy that had at least one follow-up PET scan. The predictive value of follow-up PET for detecting recurrence was 98%, all with histologic confirmation. Symptoms at the time of PET, residual mass on CT, and advance stage of disease were risk factors for recurrence. Median recurrence-free survival decreased with the presence of an increasing number of these three risk factors, and importantly, no asymptomatic patient with early-stage disease and no residual mass on CT had evidence of recurrence on PET at a mean follow-up of 38 months. Interestingly, patients with a residual mass were more likely to show recurrence on a PET scan done in the first 24 months of follow-up, whereas after 24 months, the presence of symptoms at the time of PET scanning was more predictive of recurrence. The authors concluded that while PET reliably detects recurrent HL, follow-up with PET/CT may best be based on risk factors. This approach would consider the important concerns of increasing radiation exposure due to medical imaging as well as economic cost.
In summary, the current evidence does not support the routine use of PET for follow-up of patients with lymphoma, and PET is not included as part of routine follow-up in current clinical guidelines [10, 99]. The Lugano criteria accordingly do not recommend routine surveillance imaging especially in patients with HL and DLBCL . In patients with clinical signs and in the setting of clinical trials, a CT scan can be performed for follow-up. For indolent lymphomas, the Lugano criteria recommend judicious use of follow-up scans . Emerging data suggests that PET for surveillance is possibly beneficial for a subset of patients as discussed above. More studies are needed to further define this subset and to evaluate the effects of follow-up PET on patient management, outcomes, and cost-effectiveness. Additionally, since CT surveillance is commonly applied and since PET/CT is more accurate than CT in nearly all studies, logical widespread clinical practice includes using PET/CT for follow-up of patients with NHL, especially those at high risk for recurrence.
Tracers Beyond FDG
Although FDG is the only current PET tracer approved and routinely used in the evaluation of patients with lymphoma, several radiolabeled amino acid tracers have also been investigated. Carbon-11 (11C)-methionine, an essential amino acid needed for protein and polyamine synthesis and transsulfuration and transamination reactions, has also been evaluated in a limited number of studies [167, 263, 264, 265, 266]. 11C-methionine is taken up by all grades of lymphoma (HL and NHL) with a reported sensitivity of 97% for disease detection in a single study of 32 patients . The continuum of uptake between low- and high-grade NHL seen with FDG is not as apparent with 11C-methionine using semiquantitative measures like SUV, but can be found with more intensive kinetic analysis . 11C-methionine performed equally well compared to FDG for staging lymphoma, and uptake in untreated patients was not associated with outcome [265, 266]. Other limitations of 11C-methionine are the need for an on-site cyclotron due to the 20 min half-life of 11C and normal biodistribution in abdominal organs obscuring tumor sites. A current study at St. Jude Children’s Research Hospital, Memphis, TN, is investigating methionine PET in a variety of tumor types, including lymphoma .
More recently, the thymidine analog 3′-[(18 F)fluoro-3′-deoxythymidine (FLT) has been investigated [268, 269, 270]. FLT uptake reflects thymidine kinase activity and the fraction of cells in S-phase and is an indirect measure of proliferation . In the first human studies, FLT uptake was observed in indolent and aggressive NHL which was slightly less than FDG uptake in lymphoma lesions [268, 269]. FLT discriminated indolent from aggressive NHL (area under the curve 0.98) better than FDG (area under the curve 0.78) . There was a high correlation between FLT SUV and the proliferation index Ki67 . One limitation of FLT imaging in lymphoma is the high normal accumulation of the tracer in several normal organs (hematopoietic bone marrow, liver, spleen) but particularly the hematopoietic bone marrow (SUV 6–12 range) [268, 269] where disease may be missed .
Kasper et al.  prospectively evaluated 48 patients with HL (n = 15) and NHL (n = 10 indolent, n = 23 aggressive) at the end of chemotherapy to test the prognostic ability of FLT PET and FDG-PET in this setting. The authors reported that both tracers were predictive of outcome (PET positive = worse prognosis) and the combination of tracers did not provide additional information. However, the study is limited in that very heterogeneous treatment regimens were used.
Several preclinical models have shown that FLT PET may be useful for evaluating early response of lymphoma to therapy [272, 273, 274, 275, 276]. Reduced proliferation was shown as soon as 24 h after cytotoxic therapy in one high-grade lymphoma xenograft mouse model . The time course and extent of the anti-proliferation effect may be dependent on the agent employed [272, 273, 275]. For example, a transient rise in FLT uptake (after a 2-day decline) was observed in a mantle cell mouse model of NHL after mTOR inhibition with rapamycin . The pattern of FLT uptake partially paralleled cyclin D1 expression. Larger declines in FLT uptake were seen after cytotoxic therapy than after immunotherapy in animal models and in a single human study [272, 275].
These results are promising, and there are several ongoing clinical trials further evaluating the safety and role of FLT PET in patients with lymphoma. Some are assessing the overall safety and usefulness of FLT PET and include patients with lymphoma and other hematologic or solid tumors [277, 278, 279]. In a recent prospective study of 65 patients with aggressive lymphoma treated with four cycles of R-CHOP and three cycles of ICE, FLT PET was performed at baseline and after one to two cycles of chemotherapy and FDG-PET at baseline, after cycle 4 and at end of therapy. The study found that interim FLT PET was predictive of PFS and OS. Interim FLT PET had high negative predictive value for identifying patients with good prognosis. However, the positive predictive value though slightly better than FDG-PET was still very low. Volumetric parameters were not associated with PFS and OS. The study concluded that FLT PET could help design risk-adapted therapies due to the high negative predictive value .
Additional Challenges and Limitations in the Interpretation of FDG-PET in Lymphoma
The FDG-PET and PET/CT techniques have limitations, and confounding factors can make image interpretation challenging. As previously stated, the system resolution of the scanner limits the ability of both FDG-PET and PET/CT to detect small lesions. Most modern scanners have resolutions of about 0.5–1 cm . Larger lesions are not only more readily detected, but quantification of tumor metabolism and tumor size is more reliable.
Adjunctive hematopoietic cytokines reduce the incidence of chemotherapy-induced neutropenia and its associated infectious complications in patients with nonmyeloid malignancies. Granulocyte colony-stimulating factor (G-CSF) administration before FDG-PET scanning results in altered FDG biodistribution, such as increased FDG visualization in the bone marrow and spleen [283, 284]. Consequently, disease in or just adjacent to the bone marrow or spleen may be masked. In these cases, review of images at multiple intensity levels on the computer screen and anatomic images for abnormalities helps the reader to avoid misinterpretation. In addition, G-CSF may decrease the bioavailability of FDG for (residual) tumor which could result in underestimation of the amount of residual disease post-therapy . The effects of G-CSF are most pronounced closer to the time of administration, but can last up to 28 days . As with chemotherapy, it is probably ideal to wait a minimum of 7–10 days after G-CSF administration before obtaining a post-therapy PET, but the therapeutic schedule should be considered and not delayed. Erythropoietin also increases FDG uptake in the bone if administered just prior to scanning .
FDG-PET is a useful noninvasive imaging modality for the evaluation of patients with both HL and NHL. A baseline PET/CT scan is more accurate for primary lymphoma staging than anatomic imaging, and obtaining one often facilitates future interpretation of post-therapy scans by defining the initial sites of disease. Post-therapy PET provides valuable functional and prognostic information and is probably most beneficial in patients with initially FDG-avid tumor. Post-therapy scan results can help define future management decisions as curative or palliative. Knowledge of lymphoma type and clinical history (interval therapy, surgery, concurrent illness, and drug administrations) is critical for accurate image interpretation.
Currently, interim PET scans are best utilized in the clinical trial setting where results can influence decisions along a management tree. Numerous clinical trials are ongoing evaluating interim PET scanning, and the results of these studies should provide further insight into the optimal use of PET/CT for “risk-adapted” therapy. Work on standardization of PET response criteria is ongoing.
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