Imaging Analysis

Does the degree of FDG uptake on PET/CT correlate with histological grade in follicular lymphoma?

A 76-year-old woman was referred to oncology with new palpable left axillary lymph node. Her past medical history was significant for marginal zone lymphoma that was diagnosed in 1999 (received chemotherapy), hypertension and type 2 diabetes. Her ECOG performance status was 2 and physical exam was significant for 1.5 cm left axillary lymph node. Her labs showed white blood cell count of 5.9, hemoglobin of 13.4, platelets of 232, Bun/Cr 22/0.9 and LDH 574.

Her initial staging PET/CT showed 1.2 cm × 0.6 cm left cervical lymph node with maximum standard uptake value (SUV) of 2.1, 1.1 cm × 2 cm left axillary lymph node with a maximum SUV of 4.1, hypermetabolic activity in the spleen with a maximum SUV of 4.1, abdominal lymphadenopathy around the superior mesenteric artery measured 3.2 cm × 6.7 cm × 9 cm with a SUV ranging from 4.5 to 10.4, a second nodal mass in the lower region measured 1.6 cm × 2.7 cm × 5.4 cm with a maximum SUV of 6.3 and 8 mm left external iliac node, which was not significantly hypermetabolic. She underwent a core biopsy of the abdominal nodal mass (tissue was obtained from the area with maximum SUV), and pathology showed benign lymphoid tissue and flow cytometry was limited due to the presence of few monoclonal B cells. She subsequently underwent a core biopsy of left axillary lymph node, which was nondiagnostic.

A repeat PET/CT was done four months later that showed interval increase in size of the left cervical lymph node to 1.8 cm × 1.2 cm with a maximum SUV of 4.6, left axillary lymph node 1.1 cm × 2 cm (unchanged) with an increased maximum SUV of 5.0, abdominal lymphadenopathy around the superior mesenteric artery measured 3.2 cm × 6.7 cm × 9 cm, unchanged in size but with interval increase in SUV from 4.5-10.4 to 19.5, increased second nodal mass to 4.7 cm × 4.6 cm × 10 cm with an increased SUV to 16.2, left external iliac lymph node 8 mm (unchanged), new left inguinal lymph node 1.4 cm with a SUV of 4.2 and resolution of hypermetabolic activity in the spleen. The patient underwent laparoscopic guided biopsy of abdominal nodal mass and pathology showed a diffuse infiltrate of small lymphoid cells in fibrous and adipose tissue. Immunohistochemical studies showed neoplastic B-cells CD20+, CD23partial+, BCL6+, BCL2+, CD5 negative, CD43 negative, cyclin D1 negative and CD 10 equivocal. The proliferation marker Ki67 was low (<10%). Flow cytometry showed a population of Monoclonal B-cells of approximately 20% being CD10+dim, CD19+dim, CD20+, CD22+, CD5-, Kappa+ and Lambda-. The overall findings favored low-grade follicular lymphoma. Bone marrow showed no evidence of lymphoma.

She has low grade follicular lymphoma by histology with no B symptoms, no cytopenias and normal LDH. Given the performance status and increase in SUV in the lymph nodes within just a few months, her treatment options include enrollment into a clinical trial or R-CVP while waiting for treatment records from 1999.

Figure 1: PET/CT examination demonstrates hypermetabolic activity
Figure 1: PET/CT examination demonstrates hypermetabolic activity (yellow circle) associated with a hypermetabolic left axillary lymph node in a patient with follicular cell lymphoma. The top set of images taken from 4/22/08 and the bottom set of images taken from 8/5/08 demonstrate an interval increase in the SUV from 4.2 to 5.0.

Upper left image is axial CT scan, upper right image is corresponding PET image, lower left image is fusion image containing PET images displayed on a color scale and CT images displayed on a gray scale. Lower right image is maximum intensity project image of whole body PET study.


Figure 2: Initial PET/CT examination demonstrates hypermetabolic activity
Figure 2: Initial PET/CT examination demonstrates hypermetabolic activity (yellow circle) associated with enlarged retroperitoneal lymph nodes. There has been interval increase in the hypermetabolic activity from an SUV of 1.96 in 4/22/08 (top) when compared to an SUV of 8.09 in 8/5/08 (bottom). Display convention is the same as Figure 1.

Figure 3: PET images from 4/22/08 demonstrate increased metabolic activity
Figure 3: PET images from 4/22/08 demonstrate increased metabolic activity throughout the entire bone marrow involving the axial and appendicular skeleton, suspicious for bone marrow involvement. Bone marrow biopsy was consistent with follicular lymphoma.

Source: M. Ghsani

DISCUSSION

The initial evaluation of the patient with non-Hodgkin’s lymphoma is to establish the precise histologic subtype, staging and prognostic score. NHLs can be further divided into indolent (follicular, small cell lymphocytic lymphoma, marginal zone lymphoma, lymphoplasmacytic, mycosis fungoides), aggressive types (diffuse large B-cell, mantle cell, peripheral T-cell, anaplastic large cell lymphoma), and highly aggressive (Burkitt-type, lymphoblastic). NHL is staged as per the Ann Arbor staging system.

Since the introduction of computed tomography, technological advances in imaging have largely replaced staging laparotomy and nodes greater than 1 cm in short axis are generally considered positive for malignancy. Traditionally, 67Gallium-citrate (Ga) has been widely used as a functional imaging tool to evaluate viable tumors in patients with history of treated lymphoma and is proven to be useful in differentiating benign tissue vs. residual disease while demonstrating 90% sensitivity and 93% specificity.

Widespread use of PET and PET/CT using radio labeled glucose analog fluorine-18-deoxyglucose (18F FDG) as a tumor marker has replaced gallium scanning in this application.

PET is highly sensitive in detecting nodal and extranodal involvement of common types of lymphoma (eg, diffuse large B-cell NHL, follicular NHL, mantle cell NHL, HL). Routinely used 18FFDG avidity has a sensitivity that exceeds 80% and a specificity of about 90%, which is superior to CT. PET scan upstages disease in 15% to 20% of patients. However, the impact of therapy is less than 8% and not routinely recommended for initial staging due to the very little change in management. PET scan is generally used in conjunction with a diagnostic CT as a PET/CT examination, which is generally performed at the time of initial diagnosis as a staging exam as well as a baseline examination prior to initiation of therapy. During therapy and particularly upon completion of therapy, PET/CT is useful in distinguishing viable tumor from necrosis or fibrosis. In general, PET/CT has a consistently high negative predictive value averaging about 85% across studies including patients with HL and/or diffuse large B-cell NHL. There are data in recent literature demonstrating usefulness of PET/CT in aggressive lymphoma in assessing response to therapy three weeks after completion of chemotherapy and preferably six to eight weeks after chemotherapy or chemoimmunotherapy and eight to 12 weeks after radiation or chemoradiatiotherapy. The role of PET/CT for response assessment of aggressive NHL subtypes other than DLBCL and of indolent and mantle-cell lymphomas, is less clear.

Usefulness of PET/CT in assessment of transformation in indolent lymphomas has not been clearly defined despite its higher incidence and prevalence. In assessment of this application, studies have suggested that a maximum SUV of more than 10 is highly associated with aggressive behavior but a latter study showed that the intensity of the radionuclide uptake is independent of histological grading. Given the risk of histological transformation of follicular lymphoma to aggressive lymphoma in order of 17% to 22% at five years and 28% to 31% at 10 years, further studies are warranted in defining 18FFDG avidity for differentiating various grades of follicular lymphoma and histological transformation. The above case illustrates limitation of PET/CT in this application, with rapidly increasing size and 18FFDG avidity in one particular nodal site while the histology is still of low grade follicular lymphoma. However, there still remains the possibility that histologic transformation is not uniform throughout the suspicious lymph node and cytologic sampling from a given site within the lymph node may not necessarily represent the highest tumor grade in that lymph node. Therefore, this patient should be followed closely for assessment of interval progression in the future.

Munir Ghesani, MD, is Associate Clinical Professor of Radiology at Columbia University College of Physicians and Surgeons and Attending Radiologist at St. Luke’s-Roosevelt Hospital Center.

Vamsee Torri, MD, is a Chief Fellow in Hematology/Oncology at St. Luke’s-Roosevelt Hospital Center.

Robert Chen, MD, is a Resident in Radiology, Beth Israel Medical Center.

For more information:

  • Kwee TC, Kwee RM, Nievelstein RA . Imaging in staging of malignant lymphoma: a systematic review. Blood. 2008;111:504-516.
  • Seam P, Juweid ME, Cheson BD. The role FDG-PET scans in patients with lymphoma. Blood. 2007;110:3507-3516.
  • Juweid ME, Strooants S, Hoekstra OS, et al. Use of positron emission tomography for response assessment of lymphoma: consensus of the imaging subcommittee of international harmonizing project in lymphoma. J Clin Oncol. 2007;25:571-578.
  • NCCN Non-Hodgkin’s Lymphoma guidelines version 3.2008.
  • Schoder H, Noy A, Gonen M et al. Intensity of 18fluorodeoxyglucose uptake in positron emission tomography distinguishes between indolent and aggressive non-Hodgkin’s lymphoma. J Clin Oncol. 2005;23:4643-4651.
  • Wohrer S, Jaeger U, Kletter K, et al. 18F-fluorodeoxy-glucose positron emission tomography (18F-FDG-PET) visualizes follicular lymphoma irrespective of grading. Ann Oncol. 2006;17:780-784.

A 76-year-old woman was referred to oncology with new palpable left axillary lymph node. Her past medical history was significant for marginal zone lymphoma that was diagnosed in 1999 (received chemotherapy), hypertension and type 2 diabetes. Her ECOG performance status was 2 and physical exam was significant for 1.5 cm left axillary lymph node. Her labs showed white blood cell count of 5.9, hemoglobin of 13.4, platelets of 232, Bun/Cr 22/0.9 and LDH 574.

Her initial staging PET/CT showed 1.2 cm × 0.6 cm left cervical lymph node with maximum standard uptake value (SUV) of 2.1, 1.1 cm × 2 cm left axillary lymph node with a maximum SUV of 4.1, hypermetabolic activity in the spleen with a maximum SUV of 4.1, abdominal lymphadenopathy around the superior mesenteric artery measured 3.2 cm × 6.7 cm × 9 cm with a SUV ranging from 4.5 to 10.4, a second nodal mass in the lower region measured 1.6 cm × 2.7 cm × 5.4 cm with a maximum SUV of 6.3 and 8 mm left external iliac node, which was not significantly hypermetabolic. She underwent a core biopsy of the abdominal nodal mass (tissue was obtained from the area with maximum SUV), and pathology showed benign lymphoid tissue and flow cytometry was limited due to the presence of few monoclonal B cells. She subsequently underwent a core biopsy of left axillary lymph node, which was nondiagnostic.

A repeat PET/CT was done four months later that showed interval increase in size of the left cervical lymph node to 1.8 cm × 1.2 cm with a maximum SUV of 4.6, left axillary lymph node 1.1 cm × 2 cm (unchanged) with an increased maximum SUV of 5.0, abdominal lymphadenopathy around the superior mesenteric artery measured 3.2 cm × 6.7 cm × 9 cm, unchanged in size but with interval increase in SUV from 4.5-10.4 to 19.5, increased second nodal mass to 4.7 cm × 4.6 cm × 10 cm with an increased SUV to 16.2, left external iliac lymph node 8 mm (unchanged), new left inguinal lymph node 1.4 cm with a SUV of 4.2 and resolution of hypermetabolic activity in the spleen. The patient underwent laparoscopic guided biopsy of abdominal nodal mass and pathology showed a diffuse infiltrate of small lymphoid cells in fibrous and adipose tissue. Immunohistochemical studies showed neoplastic B-cells CD20+, CD23partial+, BCL6+, BCL2+, CD5 negative, CD43 negative, cyclin D1 negative and CD 10 equivocal. The proliferation marker Ki67 was low (<10%). Flow cytometry showed a population of Monoclonal B-cells of approximately 20% being CD10+dim, CD19+dim, CD20+, CD22+, CD5-, Kappa+ and Lambda-. The overall findings favored low-grade follicular lymphoma. Bone marrow showed no evidence of lymphoma.

She has low grade follicular lymphoma by histology with no B symptoms, no cytopenias and normal LDH. Given the performance status and increase in SUV in the lymph nodes within just a few months, her treatment options include enrollment into a clinical trial or R-CVP while waiting for treatment records from 1999.

Figure 1: PET/CT examination demonstrates hypermetabolic activity
Figure 1: PET/CT examination demonstrates hypermetabolic activity (yellow circle) associated with a hypermetabolic left axillary lymph node in a patient with follicular cell lymphoma. The top set of images taken from 4/22/08 and the bottom set of images taken from 8/5/08 demonstrate an interval increase in the SUV from 4.2 to 5.0.

Upper left image is axial CT scan, upper right image is corresponding PET image, lower left image is fusion image containing PET images displayed on a color scale and CT images displayed on a gray scale. Lower right image is maximum intensity project image of whole body PET study.


Figure 2: Initial PET/CT examination demonstrates hypermetabolic activity
Figure 2: Initial PET/CT examination demonstrates hypermetabolic activity (yellow circle) associated with enlarged retroperitoneal lymph nodes. There has been interval increase in the hypermetabolic activity from an SUV of 1.96 in 4/22/08 (top) when compared to an SUV of 8.09 in 8/5/08 (bottom). Display convention is the same as Figure 1.

Figure 3: PET images from 4/22/08 demonstrate increased metabolic activity
Figure 3: PET images from 4/22/08 demonstrate increased metabolic activity throughout the entire bone marrow involving the axial and appendicular skeleton, suspicious for bone marrow involvement. Bone marrow biopsy was consistent with follicular lymphoma.

Source: M. Ghsani

DISCUSSION

The initial evaluation of the patient with non-Hodgkin’s lymphoma is to establish the precise histologic subtype, staging and prognostic score. NHLs can be further divided into indolent (follicular, small cell lymphocytic lymphoma, marginal zone lymphoma, lymphoplasmacytic, mycosis fungoides), aggressive types (diffuse large B-cell, mantle cell, peripheral T-cell, anaplastic large cell lymphoma), and highly aggressive (Burkitt-type, lymphoblastic). NHL is staged as per the Ann Arbor staging system.

Since the introduction of computed tomography, technological advances in imaging have largely replaced staging laparotomy and nodes greater than 1 cm in short axis are generally considered positive for malignancy. Traditionally, 67Gallium-citrate (Ga) has been widely used as a functional imaging tool to evaluate viable tumors in patients with history of treated lymphoma and is proven to be useful in differentiating benign tissue vs. residual disease while demonstrating 90% sensitivity and 93% specificity.

Widespread use of PET and PET/CT using radio labeled glucose analog fluorine-18-deoxyglucose (18F FDG) as a tumor marker has replaced gallium scanning in this application.

PET is highly sensitive in detecting nodal and extranodal involvement of common types of lymphoma (eg, diffuse large B-cell NHL, follicular NHL, mantle cell NHL, HL). Routinely used 18FFDG avidity has a sensitivity that exceeds 80% and a specificity of about 90%, which is superior to CT. PET scan upstages disease in 15% to 20% of patients. However, the impact of therapy is less than 8% and not routinely recommended for initial staging due to the very little change in management. PET scan is generally used in conjunction with a diagnostic CT as a PET/CT examination, which is generally performed at the time of initial diagnosis as a staging exam as well as a baseline examination prior to initiation of therapy. During therapy and particularly upon completion of therapy, PET/CT is useful in distinguishing viable tumor from necrosis or fibrosis. In general, PET/CT has a consistently high negative predictive value averaging about 85% across studies including patients with HL and/or diffuse large B-cell NHL. There are data in recent literature demonstrating usefulness of PET/CT in aggressive lymphoma in assessing response to therapy three weeks after completion of chemotherapy and preferably six to eight weeks after chemotherapy or chemoimmunotherapy and eight to 12 weeks after radiation or chemoradiatiotherapy. The role of PET/CT for response assessment of aggressive NHL subtypes other than DLBCL and of indolent and mantle-cell lymphomas, is less clear.

Usefulness of PET/CT in assessment of transformation in indolent lymphomas has not been clearly defined despite its higher incidence and prevalence. In assessment of this application, studies have suggested that a maximum SUV of more than 10 is highly associated with aggressive behavior but a latter study showed that the intensity of the radionuclide uptake is independent of histological grading. Given the risk of histological transformation of follicular lymphoma to aggressive lymphoma in order of 17% to 22% at five years and 28% to 31% at 10 years, further studies are warranted in defining 18FFDG avidity for differentiating various grades of follicular lymphoma and histological transformation. The above case illustrates limitation of PET/CT in this application, with rapidly increasing size and 18FFDG avidity in one particular nodal site while the histology is still of low grade follicular lymphoma. However, there still remains the possibility that histologic transformation is not uniform throughout the suspicious lymph node and cytologic sampling from a given site within the lymph node may not necessarily represent the highest tumor grade in that lymph node. Therefore, this patient should be followed closely for assessment of interval progression in the future.

Munir Ghesani, MD, is Associate Clinical Professor of Radiology at Columbia University College of Physicians and Surgeons and Attending Radiologist at St. Luke’s-Roosevelt Hospital Center.

Vamsee Torri, MD, is a Chief Fellow in Hematology/Oncology at St. Luke’s-Roosevelt Hospital Center.

Robert Chen, MD, is a Resident in Radiology, Beth Israel Medical Center.

For more information:

  • Kwee TC, Kwee RM, Nievelstein RA . Imaging in staging of malignant lymphoma: a systematic review. Blood. 2008;111:504-516.
  • Seam P, Juweid ME, Cheson BD. The role FDG-PET scans in patients with lymphoma. Blood. 2007;110:3507-3516.
  • Juweid ME, Strooants S, Hoekstra OS, et al. Use of positron emission tomography for response assessment of lymphoma: consensus of the imaging subcommittee of international harmonizing project in lymphoma. J Clin Oncol. 2007;25:571-578.
  • NCCN Non-Hodgkin’s Lymphoma guidelines version 3.2008.
  • Schoder H, Noy A, Gonen M et al. Intensity of 18fluorodeoxyglucose uptake in positron emission tomography distinguishes between indolent and aggressive non-Hodgkin’s lymphoma. J Clin Oncol. 2005;23:4643-4651.
  • Wohrer S, Jaeger U, Kletter K, et al. 18F-fluorodeoxy-glucose positron emission tomography (18F-FDG-PET) visualizes follicular lymphoma irrespective of grading. Ann Oncol. 2006;17:780-784.