• Hodgkin's disease;
  • non-Hodgkin's lymphoma;
  • 2-[F-18]fluoro-2-deoxy-D-glucose (FDG);
  • PET;
  • residual masses


  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

The prognostic value of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in the assessment of post-treatment residual masses in patients with Hodgkin's disease (HD) or non-Hodgkin's lymphomas (NHL) was evaluated. We prospectively studied 58 patients with HD (n = 43) or NHL (n = 15) who had post-therapeutic complete remission with residual masses (CRu) indicated by computerized tomography. Analysis of 62 residual locations by FDG-PET was performed separately for HD and NHL. Patients with a PET-positive residual mass [standardized uptake value (SUV) > 3] had a recurrence rate of 62·5% (5/8 patients), whereas patients with PET-negative residual mass (SUV ≤ 3·0) showed a recurrence rate of 4% (2/50 patients, P = 0·004). A positive FDG-PET study correlated with a significantly poorer progression-free survival (P < 0·00001). No recurrence occurred in any of the 39 HD patients with a negative PET scan (negative predictive value, 100%). Four out of four NHL patients with a positive PET study relapsed (positive predictive value, 100%). In conclusion, FDG-PET is a suitable non-invasive method with a high degree of accuracy in the prediction of early recurrence in lymphoma patients with CRu.

Despite the good response to therapy, residual mass can be demonstrated radiologically in up to 80% of patients with Hodgkin's disease (HD) and in up to 40% of non-Hodgkin's lymphoma (NHL) patients after completion of treatment (Radford et al, 1988; Surbone et al, 1988). To account for the difficulty in assessing residual mass viability, the Cotswolds Meeting led to a new category for evaluation of treatment response: complete remission unconfirmed/uncertain (CRu) (Lister et al, 1989), for which the relapse risk is reported to be about 20% (Jochelson et al, 1985; Canellos, 1988; Radford et al, 1988; Surbone et al, 1988). The management of these residual masses is a dilemma for the oncologist. Some patients might receive unnecessary additional treatment and are thus exposed to avoidable early and late toxicity.

Owing to this diagnostic dilemma, there are high expectations of positron emission tomography (PET) with the radioactively labelled glucose analogue 2-[F-18]fluoro-2-deoxy-D-glucose (FDG) which enables quantitative measurement of glucose metabolism in tumour tissue (Haberkorn et al, 1993; Steinert et al, 1995; Rigo et al, 1996; Wahl, 1999; Avril et al, 2000; Flamen et al, 2000; Halter et al, 2000; Shah et al, 2000). The FDG accumulation is directly correlated with the raised glucose metabolism of malignant cells (Warburg, 1956; Gallagher et al, 1978). As it enables detection of viability, FDG-PET appears to be especially suitable for the differentiation of active lymphoma tissue and inactive scar tissue. To date, there have only been a few prospective studies on the evaluation of residual masses after lymphoma therapy (Kostakoglu & Goldsmith, 2000). To our knowledge, no study group has differentiated between HD and NHL to assess the diagnostic accuracy for detection of active residual lymphoma. Therefore, we initiated this prospective study to enable a separate investigation of the prognostic value of PET for both lymphoma entities.

Patients and methods

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

Patients The single centre study comprised 58 consecutive patients with primary or recurrent histologically confirmed malignant lymphoma (according to the World Health Organization (WHO) classification (Harris et al, 1999). Forty-three HD patients and 15 NHL patients with a median age of 34 years (range 17–69 years) and 44 years (range 20–68 years), respectively, were included in the study. Post-treatment staging included contrast-enhanced computerized tomography (CT) in all patients. No patient received additional magnetic resonance imaging (MRI). The inclusion criterium was a complete remission with residual masses (CRu) of ≥ 1 cm diameter in the post-therapy CT. In patients presenting with initial bulky disease diameters of ≥ 0·5 cm were also acceptable. No patient received any further therapy after PET. The patients were observed prospectively, with the exception of seven patients (5 HD, 2 NHL) who were evaluated retrospectively. The study was approved by the local ethics committee. All patients gave their written informed consent to PET; the patient characteristics are listed in Table I.

Table I.  Patient characteristics.
Diagnosis HD NHL
  1. Chemo, chemotherapy; RCT, radiochemotherapy; HSCT, haematopoietic stem cell transplantation; NS, nodular sclerosis; MC, mixed cellularity.

Number of patients 43 15
SexMale25 6
Female18 9
Age (years)Median34 44
Range17–69 20–68
Bulky disease 30 7
Extranodal disease 10 9
Stage (Ann Arbor)I1 0
II17 6
III9 3
IV16 6
Histology: WHO classification 1999NS31Diffuse large B cell9
Not categorized2Mantle cell1
  T cell1
TherapyChemo only10 10
RCT30 4
Follow up without relapse (months)Median35·5 34
Range15–58 19–48

FDG-PET In all patients a PET study was performed from proximal femur to base of the skull and, depending on the primary location, also of the head and limbs. The 51 prospectively performed PET scans were acquired within 24 weeks (median 12 weeks, range 1–24 weeks) after completion of chemotherapy or combined modality treatment (chemotherapy and radiation). The seven patients who were retrospectively included were investigated within a median of 40 weeks (range 28–100 weeks) after completion of treatment. Patients with positive PET findings were only included in the study if the interval between the end of therapy and the PET investigation was at least 4 weeks after chemotherapy or 10 weeks after radiotherapy.

Imaging procedure The patients fasted for at least 6 h before the PET scan. Forty-five to 60 min after injection of 300–370 MBq 18FDG, the investigation was carried out with an ECAT EXACT-HR+ scanner (Siemens/CTI, TN, USA) with an axial field of view of 15·5 cm. The spatial resolution was 4·0 mm (axial) and 4·2 mm (transaxial). Six bed positions were acquired for 8 min each. A transmission scan for attenuation correction was acquired for each patient using rotating 68Ga/68Ge rod sources. Coronal, sagittal and transaxial data sets were reconstructed.

Scan interpretation The visual interpretation of findings was carried out after examining the sections in the black and white mode on a high resolution display by at least two experienced investigators in consensus. In the case of a pathologically raised FDG uptake, the findings were correlated with CT and clinical information. Pathological raised FDG uptake outside as well as in the region of the residual mass was quantitatively analysed using regions of interest (ROIs) and by determination of the standardized uptake values (SUVs) (Strauss & Conti, 1991). ROIs were drawn with isocontours around the suspicious lesion, setting the lower threshold at the level of SUV 2·0. The findings were classified into three categories: (A) highly suspicious for active lymphoma (‘positive’, mean SUV > 3), (B) no pathologically raised FDG uptake on visual assessment (‘negative’), and (C) pathologically questionable for lymphoma (‘questionable’, focally raised FDG uptake with a mean SUV ≤ 3). Prior PET studies (if available) were included in the interpretation of findings.

Follow-up PET-positive residues were either removed surgically or followed up clinically and with CT at short intervals. All patients were seen every 3 months in the first and second year and every 4 months in the third and fourth year. The follow-up comprised clinical examination, laboratory testing including erythrocyte sedimentation rate (ESR), cervical and abdominal ultrasound as well as chest radiography. CT scans of the affected regions were taken once or twice in the first year and about once a year in the further course if the residual findings remained at constant size at CT. End points of the study were either clinically or histologically confirmed recurrence or sustained CR in the follow-up period.

Statistics Sensitivity, specificity, accuracy, positive (PPV) and negative predictive values (NPV) of PET were calculated and are shown in Table II. The testing for statistical significance of the predictive value of PET was carried out using the chi-square test with continuity correction according to Yates. P-values of less than 0·05 were considered to be significant. The statistical parameters were calculated separately for findings within and outside the residual mass, as well as for HD and NHL. In addition, the influence of a positive or negative interpretation of a questionable PET finding on the prognostic value of PET was analysed separately. The progression-free survival (PFS) was calculated according to the Kaplan–Meier survival analysis and group comparison was made using the log-rank test (Sachs, 1984).

Table II.  Definitions for sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy.
SensitivityTrue-positive locations 
 ———————————————————————————× 100
 True-positive plus false-negative locations 
SpecificityTrue-negative locations 
 ———————————————————————————× 100
 True-negative plus false-positive locations 
PPVTrue-positive PET locations 
 ———————————————————————————× 100
 True-positive plus false-positive locations 
NPVTrue-negative PET locations 
 ———————————————————————————× 100
 True-negative plus false-negative locations 
AccuracyTrue-positive plus false-positive locations 
 ———————————————————————————× 100
 True- and false-positive plus true- and false-negative locations 


  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

In 58 lymphoma patients with CRu, a total of 62 residual locations could be demonstrated by CT. Four patients had two residual masses each. Table III (A) shows the locations of the residues. The diameters of the residues in the CT were between 0·5 and 10 cm. PET scans of 53 patients were evaluated for findings outside the residual mass. Table III (B) shows the locations.

Table III.  Analysed locations.
A. Sites of residual mass (CT scans).
Mediastinal lymph nodes361046
Cervical lymph nodes1 1
Supraclavicular lymph nodes112
Axillary lymph nodes1 1
Abdominal lymph nodes325
Retroperitoneal lymph nodes123
Vertebral column2 2
B. PET-positive lesions outside the residual mass.
Mediastinal lymph nodes314
Cervical lymph nodes112
Supraclavicular lymph nodes213
Axillary lymph nodes123
Abdominal lymph nodes4 4
Chest wall1 1
Scapula1 1

Hodgkin's disease: positive PET findings

Four out of 46 residues (four out of 43 patients) showed a positive PET scan. In one of the four patients with a positive PET study, there was a recurrence 13 months after the end of therapy or 6 months after PET in the area of the abdominal residual mass. The remaining three out of the four positive residual masses (all mediastinal) remained in stable CR with a follow-up of 21, 34 and 50 months and were therefore classified as false-positive. In two patients in whom the follow-up was 21 and 34 months, sternotomy was performed with resection of the residual mass. Histologically, non-viable scar tissue was shown in one case and an eosinophilic granuloma in another case. None of the 39 PET-negative residues (36 patients) led to a recurrence in the follow-up of 35·5 months (range 15–58 months). The correlation between PET findings in the residual mass and disease outcome is shown in Table IV (A). For the 43 HD patients with residual masses, the PET attained a sensitivity of 100%, a specificity and accuracy of 93%, a NPV of 100% and a PPV of 25% in prediction of a recurrence.

Table IV.  Clinical course in HD and NHL patients with CRu.
A. PET findings in the residual mass, based on patients.
PET result  Lymphoma nResidual relapse CCR
 Total 58  
Positive HD413
Total 853
Negative HD36036
Total 46145
Questionable HD303
Total 413
B. PET findings outside the residual mass, based on patients.
PET result LymphomanRelapseCCR
  1. CRu, complete response/unconfirmed; CCR, continuous complete response.

 Total 53  
Positive HD202
Total 422
Negative HD28028
Total 36135
Questionable HD11011
Total 13112

None of the 28 patients with a negative PET study outside the residual mass developed a relapse. Two PET studies which remained positive at the follow-up examination (two patients) showing lesions outside the residual mass (supraclavicular, thoracic paravertebral) were considered false-positive owing to a persistent CR with a follow-up of 34 and 50 months (Table IV B).

Hodgkin's disease: questionable PET findings

Three patients with questionable findings in the PET scan in the residual mass remained in persistent remission. In two of the three patients follow-up scans were negative. In the third case resection with histological examination showed non-viable scar tissue. In 12 patients questionable findings outside the residual masses were found (22 locations). None of these led to a recurrence. One patient showed both positive and questionable findings. He was categorized only once, in Table IV (B).

Non-Hodgkin's lymphoma: positive PET findings

In all four patients with a PET-positive residual mass (3 mediastinal, 1 abdominal) there was a clinically or CT-documented recurrence. The recurrence occurred after a median follow-up of 8 months (range 3–18 months) after the end of therapy or 6 months after PET (range 1–9). Ten out of the 11 PET-negative residual masses (nine patients) were free of recurrence in a follow-up period of 34 months (range 19–48 months). In one patient, there was a recurrence 10 months after the end of treatment (chemotherapy) in the residual mass (spleen) and locations outside the residual mass (retroperitoneal, bone marrow). This patient suffered from a type II diabetes, and the blood sugar was elevated (8·6 mmol/l, normal range 4·22–6·11) at the time of PET scan. Table IV (A) shows the correlation between PET findings in the residual mass and clinical outcome. In 15 NHL residual masses (14 patients) PET attained a sensitivity of 67%, a specificity of 100%, an accuracy of 87%, a NPV of 82% and a PPV of 100% in the prediction of recurrence.

Two patients with positive PET scans outside the residual mass relapsed in these locations (supraclavicular, axillary, mediastinal, pulmonary) and, additionally, in four PET-negative locations (2 cervical, 1 axillary, 1 osseous) within 6 months (median) after PET. Out of the eight patients with a negative PET study outside the residual mass, one developed a retroperitoneal relapse.

Non-Hodgkin's lymphoma: questionable PET findings

Two out of three questionable PET studies in three patients led to a recurrence. One finding was located in the residual mass (mediastinal), the other was located outside the residual mass (axillary). The recurrences were manifest 6 and 18 months after the end of therapy. The third questionable finding was located cervically, the patient remained in CR (45 months).

Significance of SUV for the prognostic value of PET in HD and NHL

When all PET findings with pathologically raised FDG uptake on visual evaluation were regarded as tumour recurrence, both in the residual mass and outside, PET yielded a sensitivity of 88%, a specificity of 68%, an accuracy of 71%, a PPV of 30% and a NPV of 97% (Table V). If questionable findings (SUV leqslant R: less-than-or-eq, slant 3) were classified as negative, the specificity increased from 68% to 94%, and the accuracy raised from 71% to 91%. The difference in the prognostic value was mainly caused by the reduction of the visually false-positive PET findings outside the residues.

Table V.  Significance of qualitative and quantitative findings (SUV) for the prognostic value of PET, evaluation of the findings inside and outside the residual masses, based on patients.
 Qualitative evaluationQuantitative evaluation SUV > 3
Positive predictive value30%6%86%67%25%100%
Negative predictive value97%100%88%96%100%80%

Prognostic value of PET in the evaluation of residual masses

HD and NHL patients with a positive PET study in the residual mass (SUV > 3) had a poorer prognosis (5/8 recurrences) than patients with a negative PET study (SUV ≤ 3; 2/50 recurrences). The results of the Kaplan–Meier analysis of the progression-free survival (PFS) were significantly different with regard to these two groups (P < 0·00001). Owing to the low recurrence rate in HD (1/43 patients), a subgroup analysis showed a statistically significant difference only in NHL patients. In these patients there was a significant difference in PFS in PET-positive (4/4 recurrences) compared with PET-negative findings (2/11 recurrences, P = 0·0015, Fig 1). The median follow-up of the patients in CR was 37 months (range 15–58 months, all patients).


Figure 1. Kaplan-Meier plot of the progression-free survival (PFS) curves for four NHL patients with PET-positive residual masses (SUV > 3) compared with 11 NHL patients with PET-negative residual masses (SUV leqslant R: less-than-or-eq, slant 3, P = 0·0015).

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  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

Early evaluation of treatment response for malignant lymphoma is important for the prognosis and further individual patient management. The interpretation of persistent residual masses detected by CT is a major clinical problem, especially in mediastinal and abdominal bulk. The remission status is evaluated by CT according to standardized guidelines (Cheson et al, 1999). However, on the basis of morphology (ultrasound, CT, MRI), a residual mass cannot be differentiated from scar tissue because size is not closely related to the risk of recurrence (Rodriguez-Catarino et al, 2000) and therefore a residual mass does not necessarily entail residual disease (Fuks et al, 1982; Canellos, 1988; Surbone et al, 1988; Van den Berg et al, 2000). However, Jerusalem et al (1999a) described a higher rate of recurrence in the presence of a post-therapeutic residual mass.

MRI has not been able to fulfil the expectations of a reliable distinction between malignant and fibrotic or necrotic lymphoma tissue (Hill et al, 1993; Devizzi et al, 1997; Maisey et al, 2000). The diagnostic relevance of 67Gallium scintigraphy is controversial, but appears to be helpful, particularly in patients with a mediastinal residual mass (Front et al, 1990; Salloum et al, 1997; Setoain et al, 1997; Ulusakarya et al, 1999; Zinzani et al, 1999a). However, the need of pretherapeutic baseline investigation in order to identify a gallium-avid lymphoma is a disadvantage. PET has additional important advantages compared with 67Gallium scintigraphy. It has a higher detection rate in the abdomen, the patient's radiation exposure is significantly less, and the logistical requirement is relatively minor (Stroobants et al, 1997; Zinzani et al, 1999b).

In our study, we prospectively investigated the diagnostic relevance of FDG-PET in lymphoma patients with CT-documented residual masses. The most important result of the study is the prediction of an early recurrence in lymphoma patients with post-therapeutic residual mass (accuracy 91%). With a median follow-up of 37 months, patients with a PET-positive residual mass (SUV > 3) had a rate of recurrence of 62·5% (5/8 patients), whereas PET-negative patients (SUV ≤ 3) showed a rate of recurrence of only 4% (2/50 patients; P < 0·05). The recurrences occurred after a median follow-up of 11 months after the end of therapy (median 6 months after PET). Positive PET studies correlated with a significantly poorer PFS (P < 0·00001).

The great heterogeneity of malignant lymphoma necessitated a separate evaluation of HD and NHL. The number of patients with NHL investigated prospectively with appropriate clinical correlates is quite small in the present study. A high positive predictive value (PPV) of 100% for NHL residual masses (4/4 recurrences) contrasts with the low PPV of 25% for HD residual masses. Jerusalem et al (1999b) also described relatively high PPV for NHL residues (6/6 recurrences), Mikhaeel et al (2000) reported 5/5 recurrences in NHL, and Zinzani et al (1999b) reported 13/13 recurrences in NHL with abdominal residual mass in their prospective studies. Spaepen et al (2001) reported 26/26 relapses after first-line chemotherapy in NHL with persistent abnormal FDG uptake (12/26 residual disease according to conventional diagnostic methods); in relapsing patients, the PFS was significantly shorter after a positive scan than after a negative scan.

The low PPV in HD residues in our study can be explained both by the low rate of recurrence of 2% in our HD patients (1/43 patients developed recurrence) as well as by a relatively higher rate (7%) of false-positive PET studies (3/43 patients) in this lymphoma entity. Cremerius et al (1999) showed that the PPV rises with an increased risk of recurrence (stage IV, patients with relapse, > 2 cycles of chemotherapy). However, false-positive PET results (SUV > 3) were found in three HD patients in our study. The inclusion of clinical information in PET-positive cases helps to interpret questionable findings, especially when these are located outside the residual mass. In our study, the percentage of false-positive residual findings was 5% in the positive (SUV > 3) PET scans evaluated (3/58). In three HD patients (two positive, one questionable finding in the residual mass), scar tissue was found in two cases after sternotomy, and an eosinophilic granuloma was found in one case. In other studies inflammatory processes such as pneumonia, tuberculosis or abscesses were reported as the causes of false-positive findings (Kubota et al, 1992; Strauss, 1996; de Wit et al, 1997). The thymus-gland hyperplasia that has been described in children and young adults (Weinblatt et al, 1997) did not occur in any of our cases.

The clinical impact of the SUV is controversial owing to the large range of variation of SUV in malignant lymphomas (de Wit et al, 1997; Stumpe et al, 1998; Cremerius et al, 1999). Consequently, PET findings were established exclusively on the basis of visual criteria in restaging of malignant lymphomas in most PET studies. In our study, calculation of SUV for visually suspect FDG accumulations was carried out in all scans. The cut-off of SUV > 3 used was based on the experience of other authors with various tumour entities (Patz et al, 1993; Cheon et al, 1999). Whereas a negative interpretation of questionable findings had only a minor effect on the sensitivity (88% versus 75%, not significant), the prognostic value of PET was improved. In the Hodgkin's disease group the specificity rose from 64% to 93% (P < 0·05) and accuracy from 65% to 93% (P < 0·05). This cut-off proved to be reliable, especially in findings outside the residual mass. By reduction of the numerous false-positive findings, the PPV rose from 6% to 25% in HD patients. In our study there were no significant changes for the NHL group owing to the smaller number of cases evaluated. Negative PET findings were highly predictive for the absence of disease recurrence (HD 100%, NHL 88%) in both tumour entities in our study. This is consistent with the results of earlier studies (de Wit et al, 1997; Bangerter et al, 1998; Spaepen et al, 2001). One false-negative result which may be attributed to a diabetic situation (Lindholm et al, 1993) was found in a NHL patient. A negative PET scan is an important contribution in the management of these patients owing to its prognostic value. It may help to obviate further treatments and may prolong the intervals between CT scans. The fear of patients that their disease will recur at the site of the residual mass might be reduced by negative PET scan.

In summary, our results indicate that FDG-PET could be used as a helpful component of therapy assessment in patients with CRu. We propose that all PET scans should comprise attenuation correction including calculation of SUV in order to minimize false-positive findings, especially in HD patients. However, owing to the small number of prospective studies available, present conventional radiological investigations remain indispensable.


  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. References
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