Eur J Nucl Med Mol Imaging DOI 10.1007/s00259-013-2624-3

ORIGINAL ARTICLE

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F-FDG PET/CT impact on testicular tumours clinical management

Valentina Ambrosini & Giorgia Zucchini & Silvia Nicolini & Annalisa Berselli & Cristina Nanni & Vincenzo Allegri & Andrea Martoni & Rubello Domenico & Antonia Cricca & Stefano Fanti

Received: 13 June 2013 / Accepted: 31 October 2013 # Springer-Verlag Berlin Heidelberg 2013

Abstract Purpose Testicular tumour is the most common malignancy in young men. The diagnostic work-up is mainly based on morphological imaging. The aim of our study was to evaluate the clinical impact of 18F-FDG PET/CT in patients with testicular tumour. Methods We retrospectively evaluated all patients studied by 18 F-FDG PET/CT at our centre. Inclusion criteria were: pathological confirmation of testicular tumour, contrast-enhanced CT scan performed within a month of the PET/CT scan, and clinical/imaging follow-up performed at the Oncology Unit of our hospital. Overall, 56 patients were enrolled and 121 PET/ CT scans were evaluated. 18F-FDG PET/CT was performed following standard procedures and the results were compared with clinical, imaging and follow-up data. Clinicians were contacted to enquire whether the PET/CT scan influenced the patient's management. Answers were scored as follows: start/continue chemotherapy or radiotherapy, indication for surgery of secondary lesions, and clinical surveillance. Results On a scan basis, 51 seminoma and 70 nonseminoma (NS) cases were reviewed. Of the 121 cases. 32 were found to be true-positive, 74 true-negative, 8 false-positive and 6 falsenegative by PET/CT. PET/CT showed good sensitivity and specificity for seminoma lesion detection (92 % and 84 %, respectively), but its sensitivity was lower for NS forms V. Ambrosini (*) : S. Nicolini : C. Nanni : V. Allegri : S. Fanti Nuclear Medicine, S.Orsola-Malpighi University Hospital, Via Massarenti 9, 40138 Bologna, Italy e-mail: [email protected] G. Zucchini : A. Berselli : A. Martoni : A. Cricca Oncology, S.Orsola-Malpighi University Hospital, Bologna, Italy R. Domenico Nuclear Medicine, S.Maria della Misericordia Hospital, Rovigo, Italy

(sensitivity and specificity 77 % and 95 %, respectively). The PET/CT scan influenced the clinical management of 47 of 51 seminomas (in 6 chemotherapy was started/continued, in 3 radiotherapy was started/continued, in 2 surgery of secondary lesions was performed, and in 36 clinical surveillance was considered appropriate), and 59 of 70 NS (in 18 therapy/ surgery was started/continued, and in 41 clinical surveillance was considered appropriate). Conclusion Our preliminary data demonstrate the potential usefulness of PET/CT for the assessment of patients with testicular tumour. It provides valuable information for the clinical management, particularly for clinical surveillance, post-therapy assessment and when relapse is suspected. Keywords

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F-FDG . PET/CT . Seminoma . Nonseminoma

Introduction Although uncommon compared with other cancers (1–5 %), testicular tumour is nonetheless the most frequent malignancy in young men, with a peak incidence in the third and fourth decades of life [1–3]. Three main pathological forms have been described: germ cell tumours (accounting for 90 – 95 % of all tumours; mainly seminoma and non-seminoma, NS), cord stromal tumours, and miscellaneous germ cell/sex cord stromal tumours [3]. The epidemiological, pathological and clinical risk factors for testicular cancer are well known and the routine diagnostic imaging work-up is based mainly on morphological procedures including ultrasonography for identification of the primary mass, and CT for visualization of secondary lesions, while MRI is performed in selected cases [3]. At present, 18F-FDG PET/CT is not routinely performed in patients with testicular cancer. However, its value for detection of the primary tumour site, metastatic spread and early occult disease in patients with a CT-negative scan is well

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documented in many forms of solid malignant tumours (e.g. lymphoma, lung, colon, breast). The aim of our study was to evaluate the impact of 18F-FDG PET/CT results on the clinical management of patients with pathologically proven testicular tumour.

Materials and methods We retrospectively reviewed patients with testicular tumour who underwent 18F-FDG PET/CT at the Nuclear Medicine Unit, S.Orsola-Malpighi Hospital, Bologna, Italy, as part of their diagnostic work-up between January 2003 and October 2011. Patients with histological confirmation of testicular tumour, a contrast-enhanced CT (ceCT) scan performed within a month of the 18F-FDG PET/CT scan, and clinical and imaging follow-up performed at the Oncology Unit, S.Orsola-Malpighi Hospital, Bologna, Italy, were included in the study. Detailed clinical history was available in all patients. Whole-body 18F-FDG PET/CT scans were carried out following standard procedures. Briefly, 3 – 5.7 MBq/kg of 18 F-FDG was intravenously injected in patients following a 6-h fast. The uptake time was 60 min in all patients. Images were acquired on a 2-D tomograph (Discovery LS; GE) for 4 min per bed position or on a 3-D tomograph (Discovery STE; GE) for 2 min per bed position. Crosscalibration was performed using an image quality NEMA phantom. A low-dose CT scan (120 kV, 80 mA) was performed both for attenuation correction and as an anatomical map. PET/CT scans were evaluated by two nuclear medicine physicians skilled in PET/CT imaging. In patients examined after therapy PET/CT was performed 6 weeks after therapy completion. For the evaluation of 18F-FDG PET/CT studies, any area with an uptake intensity greater than background uptake that could not be identified as physiological activity (brain, heart, kidneys, bladder, urinary tract) was considered potentially to be tumour tissue. As standard of reference to finally evaluate the PET/CT results (true-positive, true-negative, falsepositive, false-negative), clinical and imaging follow-up data were employed. To evaluate the clinical impact of the PET/CT findings, all referring physicians were contacted and were asked to provide information on how patients had been managed after PET/CT and how the PET/CT results had influenced clinical decisions. Each referring physician was asked to retrieve all clinical data regarding the times before and after the scan and to report any variation in clinical management based on the PET/CT result. The answers were scored as follows: (1) start/continue chemotherapy or radiotherapy, (2) indication for surgery of secondary lesions, and (3) clinical surveillance (defined as continuation of follow-up instead of

any intervention, including chemotherapy, surgery or radiotherapy).

Results Overall 56 men were recruited (mean age 37.7±11.3, range 16 – 66 years) and 121 PET/CT scans were reviewed. On a scan basis, 51 seminoma and 70 nonseminoma (NS) cases were reviewed. NS included both pure (embryonal cell carcinoma, 11 scans; teratoma, 10 scans) and mixed NS forms (49 scans) including the simultaneous presence of seminoma and NS and/or different percentages of NS tumours, including embryonal cell carcinoma, teratoma, yolk sac tumour, choriocarcinoma and germinal cell tumour. The indications for 18FFDG PET/CT imaging (Table 1) included staging after primary surgery (16 scans, 13.2 %), restaging after therapy with positive (26 scans, 21.5 %) or negative (6 scans, 5 %) ceCT, suspicion of relapse based on either increased markers (4 scans, 3.3 %) or ceCT (33 scans, 27.3 %) findings, and follow-up (36 scans, 29.7 %). The mean follow-up time after PET was 2.9±2.3 years (range 0.01 – 8.8 years). Of the 121 cases. 32 were found to be true-positive, 74 true-negative, 8 false-positive and 6 false-negative by PET/CT.. PET/CT showed good accuracy for the detection of seminoma lesions, with an overall sensitivity and specificity of 92 % and 84 %, respectively. The sensitivity for the detection of NS forms was lower (77 %) probably as a consequence of the presence of the teratoma component (that is well known to reduce the rate of detection by FDG) but the specificity was good (95 %). False-positive and false-negative findings were related to the presence of inflammation (nodes) and to the small size of lesions (lung, liver), respectively. Considering all cases (Table 2), PET/CT led to a change in the clinical management of 106 of the 121 cases (87 %), and considering the tumour types separately, led to a change in the clinical management of 47 of 51 seminomas (92 %; in 6 chemotherapy was started/continued, Fig. 1; in 3 radiotherapy was started/continued; in 2 surgery of secondary lesions was performed; and in 36 clinical surveillance was considered appropriate),and 59 of 70 NS (84 %; in 18 therapy/surgery was started/continued; and in 41 clinical surveillance was considered appropriate). This study showed that PET/CT was particularly useful in certain clinical settings. In patients studied after therapy, the PET/CT scan excluded the presence of disease in 5 of 10 patients considered positive for seminoma by ceCT and in 9 of 16 patients considered positive for NS by ceCT. PET/CT also detected the presence of disease in one patient studied after completion of therapy considered negative for seminoma by ceCT. Another indication that was particularly useful was in the setting of suspicion of relapse based on equivocal or

Eur J Nucl Med Mol Imaging Table 1 Indications for 18F-FDG PET/CT in patients with seminoma or NS with overall sensitivity and specificity Tumour type

Seminoma

Indication

Percent

Diagnostic accuracy of PET/CT Truepositive

Truenegative

Falsepositive

Falsenegative

5.0

3

3

0

0

CT-positive CT-negative 18 CT-positive/ equivocal Increased markers 51

10 6 14.9 10

8.3 5.0 4 8.3

2 1 13 1

5 5 1 6

2 0 0 3

1 42.1

0.8 12

1 32

0 6

0 1

10

8.3

4

4

1

1

Follow-up Suspected relapse

CT-positive CT-negative 18 CT-positive/ equivocal Increased markers

16 0 14.9 23

13.2 0.0 1 19.0

4 0 17 10

9 0 0 11

1 0 0 0

3

2.5

1

0

0

1

Total

70

57.9

20

41

2

6

77 (95 % CI 0.6 – 0.9)

Staging after primary surgery Restaging after therapy Follow-up Suspected relapse

Total NS

Number

Staging after primary surgery Restaging after therapy

6

positive ceCT findings. In this clinical setting PET/CT excluded the presence of disease in 6 of 10 patients considered

Sensitivity (%)

Specificity (%)

1 0 0 0 92 (95 % CI 0.6 – 1)

84 (95 % CI 0.6 – 0.9)

2 0 2

95 (95 % CI 0.8 – 1)

positive for seminoma and in 11 of 23 patients considered positive for NS.

Table 2 Clinical impact of 18F-FDG PET/CT on patient clinical management Tumour type

Indication

Number

Percent Clinical impact of PET No Start/continue Start/continue Surgery of Clinical impact chemotherapy radiotherapy secondary lesions surveillance

Seminoma

Staging after primary surgery Restaging after therapy Follow-up Suspected relapse

NS

Total Staging after primary surgery Restaging after therapy Follow-up Suspected relapse

Total a

6 CT-positive CT-negative 18 CT-positive/ equivocal Increased markers 51 10 CT-positive CT-negative 18 CT-positive/ equivocal Increased markers 70

5.0

2

4

0

0

0

10 6 14.9 10

8.3 5.0 1 8.3

0 0 1 1

0 0 3 1

0 0 0 0

1 0 13 0

1 42.1 8.3

0.8 4 3

0 6 4

0 3 0

0 2 1

1 36 2

0

16 0 14.9 23

13.2 0.0 0 19.0

3 – 1 3

3 – 0 6a

0 – 0 –

1 – 17 2a

9 –

3 57.9

2.5 11

2 15a

1 0

– 4a

– 41

–

Following one scan both chemotherapy was started and surgery of secondary lesions was performed

9 6 8

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Eur J Nucl Med Mol Imaging Fig. 1 18F-FDG PET/CT transaxial images in a 40-year-old man studied for seminoma restaging after primary surgery (a) and after completion of therapy (b). PET/CT detected the presence of a positive node at the retroperitoneal node level (a, red arrow), therefore chemotherapy was started. PET/CT performed after therapy (b) was negative (white arrow physiological bilateral ureter activity)

Discussion Testicular tumours are relatively rare in general but represent the most common cancer in young men [3]. The worldwide incidence ranges between 0.5 and 9.9 cases per 100,000 men per year, with a peak in the third and fourth decades of life. Testicular tumours comprise several forms of disease characterized by different prognoses. While seminomatous forms are associated with a good outcome, NS tumours are generally more aggressive, often include the presence of different cell types (embryonal cell carcinoma, choriocarcinoma, teratoma, yolk sac tumour) and are characterized by a worse prognosis [4]. The presence of NS features in seminoma is also associated with a worse outcome. In the past two decades, the improvements in the early diagnosis and therapeutic protocols (including orchiectomy, radiotherapy and chemotherapy) have led to testicular tumours being considered a curable cancer. While early stages are generally associated with a cure rate approaching 100 %, in advanced stages the rate varies (from 90 % to 50 %) depending on histological type and early diagnosis [4]. Testicular tumours are generally diagnosed clinically and pathologically at surgery [4]. CT is the routine imaging modality of choice for staging, early assessment of relapse and evaluation of therapy response. However, CT relies only on

morphological criteria and therefore may be hampered by false-negative reporting especially because of its inability to detect the presence of disease in normal sized nodes and often failing to detect the presence of viable tumour cells in residual masses after therapy [5]. The causes of false positive reporting in contrast may include enlarged reactive nodes that are indistinguishable from malignant lesions [5]. An advantage of 18F-FDG PET/CT is certainly the fact that is a whole-body scan, allowing all tissues and organs to be evaluated in a single-step examination. Moreover, PET/CT can identify metabolically active tissues and therefore the presence of viable tumour cells. PET/CT has proven to be highly accurate for the detection of both the primary tumour and metastatic lesions of many forms of malignant solid tumours (e.g. lung, colon, breast) and is routinely used for staging, restaging after therapy, early detection of relapse and for disease prognosis. Although there are reports in the literature supporting the potential usefulness of PET/CT with 18FFDG for the detection of testicular tumour lesions, the number of studies investigating the clinical impact of PET/CT on the management of these patients are few and based on a limited numbers of patients. The aim of our study was to retrospectively evaluate whether PET/CT could provide valuable data for patient clinical management. Overall our data confirmed the good

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diagnostic accuracy of PET/CT in the detection of testicular tumour lesions [6]. PET/CT showed good overall sensitivity and specificity in seminoma while its sensitivity in NS forms was suboptimal. This may be explained by the prevalence of mixed forms that include the presence of a teratoma component, a condition known to reduce PET detection rate [7, 8]. In our study population, the most common causes of falsepositive reporting were the presence of inflammation at the abdominal nodal level. Metastatic spread of testicular tumours occurs mainly through the lymphatic route to the retroperitoneal nodes. Right-sided tumours spread to the aortocaval nodes and retrocaval nodes. Left-sided tumours spread to the left paraaortic nodes and preaortic nodes. Haematogenous spread is predominantly to the lungs, while other metastatic sites include the brain, the bone and the liver. The detection of small lung nodules should be interpreted with care. Reports in the literature indicate that sarcoidosis is a frequent cause of false-positive PET/CT reporting in patients with testicular cancer [9, 10]. Therefore the presence of increased tracer uptake in mediastinal nodes and/or lung nodules should be evaluated with care. A detailed clinical history focused on revealing the presence of lung parenchymal disease and respiratory function impairment, in association with a careful evaluation of other organs that are frequently involved in sarcoidosis (eyes, spleen, liver, bone, skin), should always be performed. False-negative findings were mainly due to the lesions being smaller than PET/CT spatial resolution (5 mm) and to the presence of teratoma features. Our data show that PET/CT provided relevant clinical information that allowed clinical management to be changed in about 87 % of cases. PET/CT led to chemotherapy or radiotherapy being started/continued, to surgery of secondary lesions and to clinical surveillance. In both seminoma and NS, the clinical settings in which PET/CT was particularly useful were the assessment of disease after therapy, the suspicion of relapse and in clinical surveillance. In our series, PET/CT allowed the presence of active disease to be excluded in patients with ceCT-positive seminoma and in those with ceCT-positive NS. This is likely to be because PET provides metabolic information on morphologically defined lesions, allowing differentiation between scar tissue/fibrosis and viable residual tumour cells. Data on the usefulness of PET/CT for the assessment of the presence of residual disease after therapy are conflicting [11–14]. Becherer et al. found that a positive postchemotherapy PET/ CT scan was highly predictive of viable seminoma residual tumour with significantly higher sensitivity and specificity (80 %, 100 %) than CT (73 %, 73 %) [11]. Current clinical recommendation for seminoma [3, 15] do not recommend that PET/CT be performed in early clinical stages (IB) nor staging, but consider that PET/CT should be performed at least 6 weeks after therapy for the assessment of viable residual mass in advanced disease (II/III). On the contrary, the value of PET/

CT in additional to that of conventional morphological imaging in patients with NS is still an open issue [13, 16, 17]. In fact, although there are reports in favour of the use of PET/CT in patients with NS, there is also evidence that its use has no relevant benefit. A large prospective trial including high-risk patients with NS (positive for lymphovascular invasion) and a negative 18FDG PET scan after orchiectomy or marker normalization showed an unacceptably high relapse rate, suggesting that PET scanning is not sufficiently sensitive for identifying patients at low risk of relapse [18]. Current clinical practice guidelines do not recommend the routine use of PET/CT after therapy in patients with NS forms and consider that it should be used only in clinical trials [19]. Finally, PET/CT was useful for the assessment of patients during follow-up to exclude the presence of viable tumour cells in all organs and tissues with a single-step examination. Our retrospective data also included a few patients in whom PET/CT was performed for staging (six with seminoma and ten with NS). The paucity of patients included in these subgroups does not allow clinical conclusions to be drawn. Moreover, current guidelines do not recommend the use of PET/CT for staging with the exception of clinical trials. The main limitations of 18F-FDG PET/CT are the false-negative findings in patients with micrometastases and or mature teratoma, which are a frequent component of NS tumours, and in turn, the false-positive findings in patients with inflammatory masses. In a multicentre trial in 72 patients with newly diagnosed NS, 26 % with metastases to lymph nodes, 18F-FDG PET was tested against CT for primary staging. Histological diagnosis after surgery was used as the reference standard [20]. PET was found to be superior for lymph node staging (83 % correct as compared to 71 % by CT) with higher sensitivity and specificity and negative and positive predictive values (66 %, 98 %, 78 % and 95 % for PET, and 41 %, 95 %, 67 % and 87 % for CT, respectively). The authors concluded that PET was useful in patients with an equivocal scan. In conclusion, our preliminary data indicate the potential usefulness of PET/CT for the evaluation of patients with testicular tumour, especially in those with seminoma forms. However, larger and prospective studies are needed to better ascertain the clinical value of PET/CT and the specific clinical settings in which this procedure may have an additional role to currently employed imaging modalities.

Conflicts of interest None.

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