Nuclear Medicine PET/CT Lymphomas Assessment, Protocols, and Interpretation

Anatomy and Physiology

Lymphomas are a heterogeneous group of lymphoproliferative disorders that usually cause lymph node enlargement or proliferation of other secondary lymphoid tissues. However, lymphoma can arise from any tissue or organ. Lymphomas derive from the cells or precursors of the immune system. Lymphoma is broadly classified into two major groups, Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). NHL is the most common and comprises more than 80% of the cases.[4] 

Hodgkin lymphoma is further divided into classical and nodular lymphocyte-predominant lymphoma. Classical HL is divided into four subtypes, nodular sclerosis, lymphocyte predominance, mixed cellularity, and lymphocyte depletion. Non-Hodgkin lymphoma is subdivided into aggressive and indolent lymphomas. Amongst aggressive NHL, diffuse large B cell lymphoma is the most common. Mantle cell lymphoma is a less common aggressive NHL. Follicular, marginal zone, and small-cell lymphocytic lymphomas are the indolent NHL types.[5] 

Per 2017 WHO classification, lymphoma is divided into three main categories: NK T-cell lymphoma, B-cell lymphoma, and HL.[6] Indolent lymphomas can transform into aggressive forms during the course of the disease. Excisional biopsy or incisional biopsy is recommended for adequate tissue evaluation. Optimal histologic grading cannot be performed with a fine-needle aspiration biopsy.[7]

Indications

Initial Staging

Accurate baseline staging of the lymphomas is vital for the appropriate treatment and risk prognostication. Traditionally anatomic imaging (mainly CT) was used for staging and assessing the morphological response to the treatment. Staging with CT has some limitations as it depends mainly on the size of the lymph node. Integration of FDG PET/CT has improved the initial staging with better evaluation of the smaller lesions that are normal by the size criteria.

CT has limited sensitivity for detecting extranodal disease and bone marrow involvement, as morphological changes can be very subtle. FDG PET/CT is far superior to conventional imaging in detecting extranodal disease, including head and neck lymphomas with nasopharyngeal and tonsillar involvement.[8] 

Also, PET/CT better depicts disease involving bone marrow, lungs/pleura, liver, and spleen. As PET/CT is whole-body imaging (including imaging from vertex to feet or skull base to midthigh), it not only detects more lesions but can also guide metabolically active, easily amenable sites for biopsy. Indolent lymphomas demonstrate low to no metabolic activity on the FDG PET/CT as these are slow-growing tumors. PET/CT is, therefore, not routinely used for staging indolent lymphoma. In some patients, the slow-growing indolent tumors can transform into a higher grade of disease, also known as Richter’s transformation. FDG PET/CT has high sensitivity in detecting transformed disease in these patients.[9]

Evaluation of Response to Treatment

FGD PET/CT outperforms conventional anatomic imaging in assessing response to the treatment. FDG PET/CT is routinely performed after completion of the treatment to detect any residual active disease. It is often difficult to determine on the CT whether a residual lymph node represents posttreatment fibrosis or viable residual lymphoma. Resolution of abnormal metabolic activity, even if there is residual tissue seen on CT, is consistent with a complete metabolic response. A negative PET/CT after the end of treatment excludes residual disease with a high level of certainty.[10]

FDG PET/CT is also very useful during the course of chemotherapy and is usually acquired after two cycles of treatment. The interim PET/CT scans are superior to CT as a morphological decrease in tumor size is generally slower compared to the metabolic response. Negative PET after 1 or 2 cycles of treatment is highly predictive of complete remission.

Lugano classification is routinely utilized in evaluation, staging, and response assessment in patients with lymphoma. The classification is based on the recommendations of the 11th and 12th International Conference on Malignant Lymphoma held in Lugano, Switzerland, which was attended by leading hematologists, oncologists, pathologists, radiation oncologists,  radiologists, and nuclear medicine physicians. These multispecialty providers represented major international clinical trials and cancer institutes.[7][11]

Lugano classification recommends a 5-point score for response assessment, as shown below  

Scores 1, 2, and 3 are consistent with a complete metabolic response with or without residual mass on CT. 

Scores 4 and 5 are associated with partial, stable, and progressive disease. Partial remission is described as decreased metabolic activity, and there are no new lesions. Stable disease is defined as no significant metabolic change from baseline and no new lesions. Progressive disease is present if the metabolic activity increases compared to the prior study or if there are new nodal or extranodal lesions.[5]

Surveillance 

Due to high false positive rates, routine surveillance with FDG PET/CT is not recommended after patients have achieved remission.[12] However, FDG PET/CT still plays a crucial role in evaluating relapse if the patient develops clinical symptoms.

Contraindications

There are no absolute contraindications to FDG PET/CT. Allergic reactions to FDG are extremely rare. Most PET scans are performed with a low dose without contrast CT. However, if the CT is done with iodine contrast, appropriate precautions should be taken in patients with iodine allergies.

If PET/CT scan is indicated for a pregnant patient, a risk versus benefit analysis should be done. 

PET/CT examination should be rescheduled if the patient did not follow the preparation instructions.

Equipment

FDG PET/CT is performed with a specialized scanner. Intravenous access is needed for the FDG injection. Radiotracer dose is about 8 to 15 mci (millicuries). Oral or intravenous contrast is administered depending on the imaging protocol.

Personnel

Certified nuclear medicine technologist performs the injection, imaging, and processing of the data. Image interpretation is performed by a qualified nuclear medicine physician or a nuclear radiologist.

Preparation

FDG is a glucose analog. Elevated blood glucose levels can competitively inhibit FDG uptake leading to a suboptimal or non-diagnostic scan. For this reason, patients should fast for 4 to 6 hours before the FDG injection. Parenteral feeds and dextrose-containing fluids should be stopped for 4 to 6 hours. Blood glucose levels should be checked before the FDG injection.

Patients with elevated blood sugar levels above 200 must be rescheduled. Patients should be instructed to avoid chewing gum during this time interval as the gum might contain sugar, and chewing can lead to increased FDG uptake in the muscles of mastication.

Exogenous insulin shortly before the FDG injection can lead to increased FDG uptake in the muscles and reduced tumor uptake, decreasing the study's sensitivity. Diabetic patients dependent on insulin should avoid long-acting insulin for 12 hours before the FDG administration. Short-acting insulin should be withheld for 1 to 2 hours. If possible, patients with diabetes should be scheduled in the morning.

Patients should refrain from strenuous physical activity 24 hours before the study, as exercise can lead to increased FDG uptake in the skeletal muscles.

Avoid exposure to cold during the exam and FDG uptake time. Warm blankets should be provided to avoid brown adipose tissue uptake.[13]

The patient should be well hydrated.

For females of childbearing age, pregnancy tests should be obtained as per the institutional protocol.

Technique or Treatment

After the intravenous injection of the FDG, imaging of the whole body (skull base to midthigh or vertex to feet) is obtained after an uptake period of 60 to 90 minutes.

FDG is a glucose analog and enters the cell by the same membrane transport system as glucose. After entering the cell, similar to glucose, FDG is phosphorylated by hexokinase to FDG-6-phosphate. Unlike glucose-6-phosphate, FDG-6-phosphate does not undergo further metabolism and is trapped within the cells. Most cancer cells have high glucose metabolism due to overexpression of the glucose transporters, increased hexokinase activity, and low levels of glucose-6-phosphatase. Therefore, cancer cells show increased FDG uptake. The degree of FDG uptake is expressed quantitatively by the Standardized Uptake Value (SUV).[14]

FDG is attached to Fluorine-18, which is a positron-emitting radiotracer. It is produced by a cyclotron and has a half-life of 110 minutes which allows its transport to the PET scanning centers from nuclear pharmacies or nearby cyclotrons. After intravenous injection, the tracer distributes in the body and emits a positron that interacts with a free electron and annihilates, producing two photons of energy of 511 keV at 180 degrees to each other. The PET scanner then detects the photons. The raw data is then processed using advanced algorithms to produce images.[15]

Complications

Many conditions lead to false-positive findings on PET/CT. Nuclear medicine physicians or radiologists interpreting the scan should be familiar with the pitfalls seen on the FDG PET/CT as these can have serious implications for the management of the patients.

Inflammation and infection show increased FDG uptake, which can mimic the neoplastic process. Chronic granulomatous disease is one of the most challenging causes of false-positive PET/CT. The granulomatous disease can show enlarged FDG avid lymph nodes, most commonly within the chest but essentially anywhere, and can mimic lymphoma.[16]

Brown adipose tissue (BAT) uptake in subcutaneous tissues can complicate image interpretation. BAT can be mistaken for lymph nodes and lead to false-positive results. BAT can also interfere with adequate evaluation of the underlying structures, especially in patients with neck and chest lymphadenopathy. Various pharmacological drugs can reduce the BAT uptake on FDG PET and includes ß blockers like propranolol, fentanyl, and benzodiazepines like diazepam. Avoiding exposure to cold temperatures and providing warm blankets also reduces BAT uptake.[17]

Granulocyte colony-stimulating factor (GCSF) can cause a transient increase in FDG uptake in the bone marrow and spleen. A short delay of about two weeks is recommended between the administration of GCSF and follow-up PET/CT. GCSF is a glycoprotein that stimulates the production of neutrophils and the proliferation of granulocyte. Chemotherapy can cause bone marrow suppression, and patients with neutropenia receive GCSF. GCSF is often administered as primary prophylaxis with chemotherapy to prevent febrile neutropenia.

Some chemotherapeutic drugs can cause transient increased FDG uptake in the bone marrow. A delay of 4-6 weeks after chemotherapy is recommended for the PET/CT.[18]

Benign thymic hyperplasia presents as triangular bilobed shape metabolic activity in the retrosternal anterior mediastinum on FDG PET/CT in patients less than 13 years of age. Benign thymic hyperplasia can also be seen in the patient population older than 13 years of age due to the chemotherapy-induced immunological rebound phenomenon. Thymic hyperplasia is commonly seen in children and young adults undergoing chemotherapy for lymphoma and melanoma. Hyperplasia of the thymus is also reported after treatment of other malignancies. Additional treatment and biopsy are unnecessary for metabolically active benign thymic hyperplasia.[19]

Clinical Significance

Lymphoma is the most prevalent hematologic malignancy worldwide, with Non-Hodgkin’s lymphoma being the most common subtype. According to the National Cancer Institute statistics, NHL is the seventh leading cause of cancer in the United States and accounts for 4.2 % of all cancers. HL accounts for about 0.4% of all cancers.

Some risk factors associated with the development of lymphoma include older age (HL also occurs in younger age groups), family history of lymphoma, autoimmune diseases, human immunodeficiency virus infection (HIV), and occupational exposure to chemicals like insecticides and radiation exposure.

For the optimal management of these patients, it is crucial to stage and monitor the disease with a high level of accuracy. FDG PET/CT has proven to be the imaging modality of choice in managing patients with aggressive lymphomas. FDG PET/CT is far better than CT in detecting extranodal lymphomatous disease involving bone marrow, liver, spleen, bowel, lungs, head, and neck.[20] 

Extranodal disease is indicative of a poor prognosis. Baseline PET/CT also provides prognostic information as a high level of metabolic activity is associated with an elevated LDH level and is indicative of a poor prognosis. PET/CT changes treatment staging in about 30-32% of the cases.[21]

FDG PET/CT is also superior to conventional imaging, like CT, in monitoring the therapeutic response as metabolic response occurs earlier than tumor size shrinkage. Good response to treatment on the interim PET/CT is associated with complete remission at the end of the treatment.[22] FDG PET/CT also provides a quantitative and semiquantitative assessment of tumor burden in terms of standardized uptake value, tumor volume, and total lesion glycolysis.[14]

Enhancing Healthcare Team Outcomes

Management of lymphoma, including diagnosis, baseline staging, treatment, and monitoring, requires an integrated interprofessional approach. Internationally followed Lugano recommendations were formulated by a leading team of international multispeciality physicians representing major lymphoma clinical trials centers and cancer institutes.

Referring medical oncologists and nuclear radiologists should be familiar with the appropriate indications and limitations of PET/CT. They should also be familiar with the Lugano classification and 5-point PET score. Reading physicians are recommended to include a 5-point PET score when reporting the PET/CT for lymphoma patients, as this information can be extremely valuable for medical oncologists treating the patient. 

Open and effective communication amongst the referring clinicians and imaging physicians, as well as participation in the interprofessional tumor board conferences, is highly recommended.[11]