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INTRODUCTION
Lymphoma is the most common hematological malignancy and is divided into more than 80 subtypes by the latest World Health Organization classification revised in 2016 [1]. In South Korea, lymphoma accounts for 2.3% of all newly diagnosed cancers (according to the annual report of cancer statistics in Korea), and approximately 5,216 new cases of non-Hodgkin lymphoma (NHL) and 299 new cases of Hodgkin lymphoma (HL) were diagnosed in 2018 [2].
The accurate assessment of initial disease status and therapeutic responses is critical to the optimal management of patients with lymphoma. Currently, staging of lymphoma and evaluation of treatment response are primarily performed according to the Lugano 2014 classification, and the importance of functional imaging such as 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) is increasingly being emphasized [3]. In this article, we will review Lugano classification and the role of FDG-PET/CT in the management of lymphoma.
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THE LUGANO CLASSIFICATION
In 1999, the National Cancer Institute Working Group established the first universally accepted response criteria for both NHL and HL [4], and revised in 2007 by the International Working Group to incorporate PET and bone marrow immunohistochemistry and flow cytometry [5]. As the experience of FDG-PET/CT has been gradually accumulated, FDG-PET/CT has been recognized for its definite usefulness in the evaluation of lymphoma [6]. Lymphoma staging is currently based upon the Lugano 2014 classification formulated at the 11th and 12th International Conference on Malignant Lymphomas in Lugano, Switzerland.
Initial evaluation and staging
For accurate diagnosis of various subtypes of lymphoma, an incisional or excisional biopsy is preferred to provide adequate tissue for morphology, immunohistochemistry, and additional molecular study [1]. However, a core-needle biopsy can be considered when an excisional biopsy is impossible [7].
FDG-PET/CT scanning has become the standard for staging and assessment of response in HL and FDG-avid NHL subtypes [8, 9]. A contrast-enhanced CT scan is recommended for FDG non-avid histologies and is also recommended if measuring nodes is essential or for radiotherapy planning. For patients staged with FDG-PET/CT, focal uptake in nodal and extranodal sites is considered involvement with lymphoma [10].
If an FDG-PET/CT is performed, a bone marrow biopsy (BMB) is no longer indicated for HL [11]. A BMB is only needed for diffuse large B-cell lymphoma (DLBCL) if the FDG-PET/CT is negative and identifying discordant histology is important for patient management [12]. All other lymphoma histologies are insufficient to change the standard practice, and unilateral BMB is recommended.
Combining the above, a modification of the Ann Arbor classification is recommended (Table 1). Suffixes A and B indicating the presence of symptoms of lymphoma are only required for HL, and the designation X for bulky disease is no longer necessary.
Table 1
A modified Ann Arbor staging system.
Response assessment and follow-up evaluation
Interim and end-of-treatment (EOT) assessment with FDG-PET/CT is recommended with Deauville 5-point scale (Table 2), while CT-based response is preferred for histologies with low or variable FDG-avidity [13]. EOT scans are generally performed 6–8 weeks following completion of treatment, but a different time point may be needed for regimens containing various immunological agents currently used. Metabolic response criteria using Deauville 5-point scale is given in Table 3.
Table 2
The Deauville 5-point scale.
Table 3
Metabolic response criteria using Deauville score (adapted from Lugano classification).
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CURRENT ROLE OF FDG-PET/CT IN THE MANAGEMENT OF LYMPHOMA AND FUTURE DIRECTION
Baseline FDG-PET/CT affects clinical prognostication of most subtypes of lymphoma including DLBCL, peripheral T-cell lymphoma (PTCL), follicular lymphoma (FL), and HL [6, 14-16]. In the staging of FDG-avid subtypes, FDG-PET/CT is the preferred modality for staging than CT, especially for identifying extranodal sites [10]. FDG-PET/CT removes the need for BMB in most patients of DLBCL and HL, and it allows for mapping of initial disease sites for accurate response assessment [17]. For patients with PTCL, FDG-PET/ CT identifies more disease sites and usually upstages diagnosis compared with CT, but PET-induced stage alteration rarely changes treatment strategies because most affected patients have advanced disease [18].
The predictive value of interim FDG-PET/CT has been evaluated in early or advanced-stage HL, DLBCL, PTCL, extranodal natural killer/T-cell lymphoma, and primary mediastinal B-cell lymphoma (PMBCL) [19-21]. Most previous studies have emphasized the role of interim FDG-PET/CT for confirming early response during first-line chemotherapy treatment, especially in HL [21], but an increased number of reports have recently been published focusing on relapsed or refractory disease of HL and NHL to predict the outcome of salvage treatment [19, 22].
FDG-PET/CT provides quantitative information on tumor burden. Several studies suggest that metabolic tumor volume (MTV) and tumor lesion glycolysis (TLG) are associated with worse prognosis in high-tumor burden DLBCL, PTCL, and FL [23-25]. In patients with PMBCL, TLG was an independent predictor of worse progression-free survival [26]. MTV could have an important role in developing risk-adapted approaches in NHL, and cooperative efforts for standardization of MTV measurement is warranted.
Most recently, research on PET-based quantitative evaluation of cancer using artificial intelligence (AI) and deep learning has been actively conducted [27, 28]. Multiple studies suggested AI could enhance the characterization and quantification of tumors and predict treatment response and risk stratification of recurrence [29]. Although it is still challenging to apply AI-based procedures routinely in clinical practice, it is expected that experiences and data will be gradually accumulated, and more effective clinical application of FDG-PET/CT on lymphoma will be achieved.
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CONCLUSIONS
Accurate pretreatment staging and evaluation of treatment response are critical for establishing a treatment strategy for lymphoma. Lymphoma staging and response assessment systems have evolved with advances in radiologic techniques and Lugano classification has been widely used for most subtypes NHL and HL by combining FDG-PET/CT. It is expected that the more sophisticated application of functional imaging techniques along with the development of various biologic therapeutic agents will contribute to improving the survival rate of lymphoma patients.
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