cancer testicular

1. AJR:200, June 2013 1215
from surgical pathology after radical orchiec-
tomy, the initial evaluation includes complete
history and physical examination followed by
expeditious testicular ultrasound.
Tumor Subtypes
Testicular tumors are subdivided into two
major categories: germ cell and stromal tumors.
Germ cell tumors (GCTs) account for 90–95%
of all testicular tumors and are the typical tu-
mor tissue types considered when discussing
testicular cancer. GCTs are further subdivid-
ed into seminoma and nonseminomatous GCT
(NSGCT). This division plays a critical role in
determining the approach to treatment. Sem-
inoma is an extremely radiosensitive tumor,
whereas NSGCTs respond better to surgical and
chemotherapeutic approaches. Seminoma is the
most common pure cell histology of all tumors.
However, the most common tumor type overall
is a mixed GCT, which contains elements of
multiple subtypes of GCT, including NSGCT
and seminoma.
Mixed tumors are treated as NSGCT even
in the presence of seminomatous components.
Other malignant tissue types seen as pure or
mixed histologies of NSGCT include em-
bryonal carcinoma, choriocarcinoma, tera-
toma, and yolk sac tumors. Testicular tumor
subtypes commonly present by age group:
yolk sac (0–10 years), choriocarcinoma (20–
30 years), embryonal and teratoma (25–30
years), and seminoma (30–40 years).
Tumor Markers
Multiple tumor markers are available to as-
sist with staging, prognosis, monitoring, and
Testicular Cancer: What the
Radiologist Needs to Know
Evgeniy I. Kreydin1
Glen W. Barrisford
Adam S. Feldman
Mark A. Preston
Kreydin EI, Barrisford GW, Feldman AS, Preston MA
1
All authors: Department of Urology, Massachusetts
General Hospital, Harvard Medical School, GRB 1102, 55
Fruit St, Boston, MA 02114. Address correspondence to
M. A. Preston (mpreston1@partners.org).
Genitourinary Imaging • Review
AJR 2013; 200:1215–1225
0361–803X/13/2006–1215
© American Roentgen Ray Society
T
esticular cancer represents the most
common nonhematologic malig-
nancy in men between 15 and 49
years old [1]. Although the disease
is relatively uncommon, the incidence has more
than doubled over the past four decades [2, 3].
In 2012, 8590 new diagnoses will be made and
360 deaths are expected to occur among men in
the United States. The median ages of diagnosis
and death are 33 and 41 years, respectively. The
lifetime risk of developing testicular cancer is
one in 268 men, whereas the risk of death from
the disease is one in 5000 men. Although this
disease is present in all races, the rate among
whites is nearly five times that found in African
Americans, over three times the rate in Asians,
and 1.5 times the rate in Hispanics and Native
Americans [4]. Worldwide, there is great vari-
ation in incidence among countries. The high-
est incidence is seen in Scandinavian countries
with 6.7 per 100,000 men, whereas Japan re-
ports the lowest incidence with 0.8 new diag-
noses per 100,000 men [4].
Clinical Presentation
Typical presentation includes a painless
mass in the testicle or groin. However, approx-
imately 10% of patients will have associated
tenderness on examination. Nearly one third
of patients are initially misdiagnosed with ep-
ididymitis, orchitis, or hydrocele [5]. At initial
diagnosis, approximately 20% of patients will
have metastatic disease and may present with
abdominal or back pain, malaise, or lethargy.
This is often an indication of bulky lymph-
adenopathy in the abdomen or retroperitone-
um [6]. Although definitive diagnosis is made
Keywords: CT, diagnosis, diagnostic performance,
evidence-based medicine, MRI, staging, testicular
cancer, testis cancer
DOI:10.2214/AJR.12.10319
Received November 14, 2012; accepted without revision
November 21, 2012.
FOCUS
ON:
OBJECTIVE. The purpose of this article is to review current imaging techniques and evolv-
ing technologies that are being used for detection and management of testicular cancer.
CONCLUSION. The primary goal of cancer imaging is accurate disease characterization at
diagnosis and through all stages of management. Knowledge of the disease and diagnostic perfor-
mance characteristics of each technique is critical to identify the appropriate modality for staging
disease and to monitor for treatment response and recurrence that may dictate further intervention.
Kreydin et al.
Imaging Testicular Cancer
Genitourinary Imaging
Review
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2. 1216 AJR:200, June 2013
Kreydin et al.
prediction of pathologic histology. Testicular
cancer is the only disease among genitourinary
malignancies that includes markers as a sepa-
rate category in the staging system. These mark-
ers are drawn before and after orchiectomy for
staging and prognostic information. Similarly,
they are drawn at regular intervals during treat-
ment and follow-up to monitor disease progress
and evaluate burden of disease. The three well-
established markers are α-fetoprotein (AFP),
HCG, and lactate dehydrogenase (LDH).
AFP is a glycoprotein with a half-life of 4–6
days. In the absence of testicular malignan-
cy, AFP elevation can occur in infants under
1 year old, liver dysfunction (hepatitis, cirrho-
sis, malignancy), and other nontesticular ma-
lignancies (liver, pancreatic, gastric, lung). In
testicular cancer, AFP is never present in pure
seminoma or pure choriocarcinoma.
HCG is a smaller glycoprotein and has a
half-life of 24–36 hours. In men without tes-
ticular cancer, it can also be elevated second-
ary to marijuana use. Other false-positive
results can occur in cases of elevation of lu-
teinizing hormone or more commonly from
the presence of heterophilic antibodies, both
resulting from cross-reactivity of the HCG
test. In patients with testicular cancer, HCG
is always elevated in the presence of cho-
riocarcinoma. It can also be elevated in the
presence of embryonal carcinoma, teratoma,
and up to 10% of pure seminoma.
LDH is an enzyme with a half-life of 5–7
days and can be elevated in both seminoma
and NSGCT. Elevation is typically an indica-
tion of bulky or extensive disease.
Lymphatic Drainage
Testicular tumors most commonly metas-
tasize via lymphatic drainage. However, cho-
riocarcinoma can also spread hematogenous-
ly. Testis malignancy typically disperses in a
predictable fashion throughout the native lym-
phatic system. Initial drainage is through the
inguinal ring along the spermatic cord follow-
ing the testicular vessels to the ureteral cross-
ing and dispersing in the retroperitoneum.
The retroperitoneal lymph nodes are the
most common site for metastatic disease. The
primary landing zone for tumors of the right
testis is the interaortocaval nodal group infe-
rior to the renal hilar vessels. The first echelon
of lymph nodes draining the right testis is lo-
cated in the interaortocaval area, followed by
the precaval and preaortic nodes. The prima-
ry landing zone for left-sided tumors includes
the paraaortic and preaortic lymph nodes, fol-
lowed by the interaortocaval nodes [7].
It is common to have crossover drainage
from right-sided tumors to left-sided lymph
node groups. However, drainage from left
to right has not been reported to date [7, 8].
Thorough understanding of lymphatic drain-
age has been key to developing modified sur-
gical templates for a retroperitoneal lymph
node dissection (RPLND).
Diagnosis
Sonographic imaging of the testes repre-
sents the reference standard imaging evalu-
ation, with sensitivity of near 100% when
combined with physical examination (Fig. 1).
Ultrasound can distinguish intra- and extra-
testicular lesions and is undertaken in most
cases before orchiectomy [9]. Testicular tu-
mors are typically well defined and hypo-
echoic compared with normal testicular tissue
but can be heterogeneous with calcification or
cystic changes [10]. Increased vascularity of a
lesion is not specific to testicular tumors.
In cases in which the diagnosis is in question,
additional information can be gained with MRI.
Solid testicular tumors have lower signal inten-
sity on T2-weighted MRI in contrast with the
high signal intensity of normal testicular paren-
chyma. One study evaluated MRI of the testes
before orchiectomy in 33 patients with T1- and
T2-weighted images using a 1.5-T MRI unit.
The sensitivity and specificity of MRI in dif-
ferentiating benign from malignant intratesticu-
lar lesions were 100% and 87.5%, respectively.
Furthermore, the accuracy of MRI for assigning
pathologically confirmed T category was 92.8%
[11]. The role of MRI of the testis in place of
ultrasound remains to be clearly determined.
However, it offers reliable and detailed infor-
mation in the case of equivocal ultrasound find-
ings or in the absence of a skilled sonographer.
On occasion, the initial presentation may be
a retroperitoneal mass, with testicular imaging
Fig. 1—Ultrasound
image of testis in
27-year-old man shows
well-circumscribed,
hypoechoic, solid
intratesticular mass
consistent with germ cell
tumor.
Fig. 2—Testicular
microlithiasis in 20-year-
old man. Transverse
ultrasound image of testis
shows multiple punctate
hyperechoic foci.
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3. AJR:200, June 2013 1217
Imaging Testicular Cancer
not revealing an evident lesion. In these cases,
a testicular malignancy must be considered be-
cause the primary testicular tumor may have
“burned out” and no longer be evident or it may
appear more subtle on imaging [12, 13] (Fig.
2). A more unusual presentation would be that
of an extragonadal GCT. Extragonadal GCTs
are essentially of the same histology as testic-
ular malignancies but develop outside of the
testis, commonly in the pineal gland, medias-
tinum, retroperitoneum, or sacrum [14, 15].
In either of these situations, tumor markers or
biopsy may provide insight to the diagnosis.
The finding of testicular microlithiasis (Fig.
3) is commonly present on ultrasound imaging
in patients with testicular malignancy. Histori-
cally, the contribution of testicular microlithia-
sis to the risk of malignancy has been contro-
versial; however, more recent data have shown
that the presence of microlithiasis on an oth-
erwise normal testicular ultrasound does not
predispose the patient to testicular malignan-
cy [16]. One study of sonographic screening in
1504 healthy United States Army Reserve re-
cruits revealed an incidence of testicular micro-
lithiasis of 5%, or 1000 times greater than the
incidence of testicular malignancy [17]. It ap-
pears the presence or absence of testicular mi-
crolithiasis is not significantly associated with
risk for malignancy, and there is no good evi-
dence to support a role for imaging surveillance
in the absence of additional risk factors [18, 19].
Staging
Testicular malignancy has one of the most
complete and thorough staging systems among
genitourinary cancers. It combines clinical,
pathologic, radiologic, and serum tumor mark-
er components. Staging typically relies on sur-
gical pathology of the orchiectomy specimen,
tumor markers before and after orchiectomy
(AFP, HCG, and LDH), chest radiography or
chest CT, and CT of the abdomen and pelvis.
A staging chest CT is typically performed if
there is adenopathy on the abdominal-pelvic
CT or abnormal findings on chest radiogra-
phy. Additional evaluation of bone and brain
are warranted if symptoms or clinical suspi-
cions are present [9, 20].
The staging systems commonly used are the
American Joint Committee on Cancer (AJCC)
[21] and the International Germ Cell Tumor
Consensus Conference Classification [22–25].
The AJCC staging is a TNMS-based (T = tu-
mor, N = node, M = metastases, S = serum
markers) classification because progression can
also be monitored by the level of specific serum
markers: AFP, HCG and LDH (Appendix 1).
Whereas surgical pathology determines the
T category of the neoplasm, imaging plays a
critical role in determining the N and M com-
ponents of testicular tumor staging. N cat-
egory is determined by the extent of retro-
peritoneal lymphadenopathy, and M category
describes distant metastases. Roman numeral
stage grouping divides testicular cancer into
three major groups on the basis of TNMS
characteristics: tumors limited to the testis
are stage I, those with retroperitoneal nodal
involvement are stage II, and those with dis-
tant disease are stage III [21] (Table 1).
In light of the high success rate of testicu-
lar cancer treatment, the International Germ
Cell Consensus established a system to pre-
dict progression-free survival by stratifying
patients with advanced disease into good, in-
Fig. 3—Burned-out
testicular tumor
in 24-year-old
man. Ultrasound
image of testis
shows hyperechoic
intratesticular lesion
with heterogeneous
echotexture of testicular
parenchyma, consistent
with burned-out germ
cell tumor.
TABLE 1: Testicular Cancer TNM Overall Stage Grouping [21]
Stage Tumor Node Metastases Serum Markers
Stage 0 pTis N0 M0 S0
Stage I pT1–4 N0 M0 Sx
IA pT1 N0 M0 S0
IB PT2 N0 M0 S0
pT3 N0 M0 S0
pT4 N0 M0 S0
IS Any pT/Tx N0 M0 S1–3
Stage II Any pT/Tx N1–3 M0 Sx
IIA Any pT/Tx N1 M0 S0
Any pT/Tx N1 M0 S1
IIB Any pT/Tx N2 M0 S0
Any pT/Tx N2 M0 S1
IIC Any pT/Tx N3 M0 S0
Any pT/Tx N3 M0 S1
Stage III Any pT/Tx Any N M1 Sx
Any pT/Tx Any N M1a S0
Any pT/Tx Any N M1a S1
Any pT/Tx N1–3 M0 S2
Any pT/Tx Any N M1a S2
Any pT/Tx N1–3 M0 S3
Any pT/Tx Any N M1a S3
Any pT/Tx Any N M1b Any S
Note—T = tumor, N = node, M = metastases, S = serum markers.
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4. 1218 AJR:200, June 2013
Kreydin et al.
termediate, and poor risk [22] (Table 2). This
system is based on primary tumor histology,
location, the presence or absence of nonpul-
monary visceral metastases, and serum tumor
markers. The criteria for risk category differ
slightly between seminoma and nonsemino-
ma and by the defined system. Pure semino-
ma is never classified as poor risk.
Ultrasound
Ultrasound is not recommended for use in
distant staging of testicular cancer because it
is vastly inferior to CT or MRI in assessing
the presence and burden of disease.
CT
Differentiation of stage I and stage II or
III disease can only be accomplished with
cross-sectional abdominal imaging. Because
of excellent anatomic resolution and wide-
spread availability, CT with IV and oral con-
trast administration is the reference standard
for evaluation of retroperitoneal lymphade-
nopathy (Fig. 4) and the abdominal viscera.
Staging of retroperitoneal disease depends on
nodal size. Although CT excels at identifying
and determining the diameter of retroperito-
neal lymph nodes, this modality cannot dif-
ferentiate a lymph node that is infiltrated with
malignant tissue from a lymph node that is
benign. As a result, malignant lymph nodes
are identified based on size criteria, with ma-
lignant nodes usually considered to be 8–10
mm or greater in diameter. Abdominopelvic
CT offers sensitivity of approximately 70–
80%, but this is highly dependent on nodal
size because testicular cancer has a high pro-
pensity for nodal micrometastases [26]. In
1997, Hilton et al. [26] assessed preopera-
tive CT images in 70 patients who underwent
RPLND and found that using a criterion of
lymph node diameter of 10 mm or larger as a
marker of malignancy, positive lymph nodes
were identified with sensitivity of only 37%,
although specificity of 100% was achieved
[26]. As expected, when the cutoff value was
lowered to 4 mm, the sensitivity of CT rose
to 93% at the cost of decreasing specificity
to 58%. In another recent study, the authors
recommended lowering the criterion for call-
ing a lymph node positive on CT to 7–8 mm
[27]. For 80 patients undergoing RPLND,
they were thus able to increase the sensitivity
of CT for detecting malignant lymph nodes
from 40% to 70% while maintaining speci-
ficity at 70%. In summary, nodes 8 mm or
larger should be considered suspicious, espe-
cially in higher risk patients who have lym-
phovascular invasion, a high proportion of
embryonal subtype, or T category ≥ II.
MRI
Although abdominal CT offers excellent an-
atomic resolution of the retroperitoneum, the
high dose of radiation generated and the rela-
tively young age of testicular cancer patients
have served as an impetus to evaluate MRI as
a potential modality for retroperitoneal lymph
node evaluation (Fig. 5). Two studies com-
pared CT and MRI and found similar sensitiv-
ity and specificity for detecting positive lymph
nodes between the two modalities [28, 29]. A
TABLE 2: International Germ Cell Tumor Consensus Conference Risk Classification [22]
Risk Status NSGCT Seminoma
Good All of the following: AFP < 1000 ng/mL and HCG < 5000 IU/L (1000 ng/
mL) and LDH < 1.5 times upper limit of normal; nonmediastinal
primary tumor; no nonpulmonary visceral metastases
All of the following: any primary site; normal AFP, any HCG, any
LDH; no nonpulmonary visceral metastases
Intermediate All of the following: AFP 1000–10,000 ng/mL or HCG 5000–50,000
IU/L or LDH 1.5–10 times normal; nonmediastinal primary site; no
nonpulmonary visceral metastases
Presence of nonpulmonary visceral metastases
Poor Any of the following: AFP > 10,000 ng/mL or HCG > 50,000 IU/L
or LDH > 10 times normal; mediastinal primary site; nonpulmo-
nary visceral metastases
No patients are classified as poor risk
Note—NSGCT = nonseminomatous germ cell tumor, AFP = α-fetoprotein, LDH = lactate dehydrogenase.
A
Fig. 4—Retroperitoneal lymphadenopathy in two patients.
A, CT image shows heterogeneous interaortocaval node in 46-year-old man with right-sided germ cell tumor (GCT).
B, CT image shows enlarged lymph node in paraaortic region in 37-year-old man with left-sided GCT.
B
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5. AJR:200, June 2013 1219
Imaging Testicular Cancer
more recent series published in 2009 evaluat-
ed 30 patients with testicular cancer who under-
went both CT and MRI [30]. All of the im-
ages were read by two attending radiologists
with more than 10 years of experience and a
resident in the first year of training. Using CT
as a reference standard, the authors found that
when interpreted by attending radiologists,
MRI had sensitivity of 97% and concluded
that for experienced practitioners MRI serves
as an excellent modality for retroperitoneal
lymph node staging [30]. Although these are
encouraging findings, MRI has yet to become
a mainstay in testicular cancer staging because
of its cost, prolonged scanning time, relative
unavailability, and paucity of radiologists
with sufficient experience interpreting abdom-
inal MRI. These factors are likely to improve
in the future and, together with the absence of
ionizing radiation or use of iodinated contrast
material, will make MRI a reasonable option
for use in staging evaluation.
PET/CT Imaging
Nuclear or functional imaging, such as 18F-
FDG PET, may someday offer a means of de-
tecting subcentimeter lymph nodes infiltrated
with testicular cancer. Although functional
imaging offers information different from the
anatomic imaging provided by CT or MRI,
currently used functional imaging technolo-
gy also suffers from poor ability to detect ma-
lignancy in small nodes [31, 32]. FDG PET is
not presently included in the initial staging of
testicular malignancy because there is a lack
of evidence to support its routine use [33, 34].
A multicenter European trial of 169 patients
with NSGCT showed that FDG PET was only
A
Fig. 5—29-year-old man with retroperitoneal lymphadenopathy.
A, T1-weighted MR image shows interaortocaval lymphadenopathy causing right-sided hydronephrosis.
B, T2-weighted MR image shows paraaortic lymphadenopathy.”
B
A
C
Fig. 6—23-year-old man who presented with large left testicular mass.
A and B, Radiograph of chest (A) and corresponding axial chest CT image (B) show innumerable bilateral
nodules consistent with pulmonary metastases of testicular neoplastic process. Radical orchiectomy specimen
revealed mixed germ cell tumor with components of teratoma, embryonal carcinoma, and seminoma. Patient
subsequently underwent four cycles of etoposide, ifosfamide, and cisplatin (VIP) chemotherapy.
C and D, Postchemotherapy chest radiograph (C) and axial chest CT image (D) show complete resolution of
pulmonary metastases.
B
D
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6. 1220 AJR:200, June 2013
Kreydin et al.
slightly superior to CT in detecting malignant
retro­
peritoneal lymph nodes [33]. In that study,
FDG PET was unable to achieve a negative
predictive value (NPV) of 80% determined
by the authors to be clinically significant, al-
though at 78% it was higher than the NPV of
abdominal CT, which was 67%. The authors
concluded that nuclear imaging might play a
role in cases of questionable CT results. Al-
though FDG PET may be useful in ambiguous
cases, nuclear imaging ultimately suffers from
the inability to detect mature teratoma, and it
is primarily for this reason that its use is not
recommended in routine staging [32, 35, 36].
Unfortunately, the use of functional imag-
ing in the initial staging of seminoma has not
been as rigorously evaluated and, indeed, the
most recent guidelines of the European Society
for Medical Oncology recommend against its
use in this setting [37]. Nevertheless, it appears
reasonable to assess FDG PET in initial stag-
ing of seminoma using prospective random-
ized trials because its usefulness has been sug-
gested by at least one retrospective cohort [38].
Chest Imaging
Because testicular cancer has propensity to
spread to the mediastinal lymph nodes after
reaching the retroperitoneum, chest imaging
plays an important role in initial staging (Fig.
6). CT of the chest represents the most sensi-
tive evaluation, but this is compromised by re-
duced specificity with increased false-positive
findings. A 2007 series assessed the sensitiv-
ity and specificity of chest CT in initial stag-
ing of 182 patients with seminoma and found
that CT had a higher false-positive rate while
maintaining the same sensitivity as radiog-
raphy [39]. In a similar study that compared
chest CT and radiography in both seminoma
and NSGCT, the authors found that chest ra-
diography was preferable in all patients with
seminoma and patients with NSGCT who had
normal abdominal imaging [40]. However, a
slight advantage for chest CT has been noted
among NSGCT patients who had abnormal
radiography in some studies [40, 41].
Despite these findings, there is no universal
agreement for the use of CT in chest imaging
of patients with testicular cancer. Although
the practice of foregoing chest CT is support-
ed and advocated by the National Clinical
Cancer Network (NCCN), the European As-
sociation of Urology would favor routine CT
of the chest, citing a potential to miss up to
10% of small subpleural lymph nodes that are
not visible on radiography [9, 41, 42]. Either
practice is recognized as standard of care.
Brain Imaging
Imaging of the brain as part of initial
staging is only recommended when there is
a high suspicion for brain metastases. This
situation usually arises when the patient is
neurologically symptomatic or has exten-
sive pulmonary disease. Choriocarcinoma,
the most aggressive histologic subtype, is
most prone to metastasize to distant sites,
and therefore brain imaging is probably in-
dicated in patients found to have chorio-
carcinoma in their orchiectomy specimen
and persistently elevated β-HCG. Three-di-
mensional imaging of the brain can be per-
formed either with CT or MRI; testicular
cancer metastases usually appear as hem-
orrhagic lesions that typically enhance with
contrast administration [43].
Surveillance in Patients With Stage I
Testicular Cancer
Surveillance as a management strategy
is being increasingly used in patients with
stage I seminoma and NSGCT. The impe-
tus for this practice is that approximately
72% of NSGCT and 83% of seminoma pa-
tients are cured with radical orchiectomy and
do not have disease in the retroperitoneum
or elsewhere [44]. Furthermore, even in pa-
tients who do relapse, salvage chemotherapy
is so effective that the cause-specific survival
rates for seminoma and NSGCT are approxi-
mately 100% and 98%, respectively [44].
Surveillance regimes vary by institution,
but all include serial clinical examinations, se-
rum markers, chest radiography and abdomi-
nal CT. Most tumor relapses occur in the first
6–12 months, are rare beyond 5 years, typical-
ly present in the retroperitoneum, and are usu-
ally detected on abdominal imaging [44, 45].
In the current 2012 NCCN guidelines, the fol-
low-up regimen for stage IA or IB NSGCT pa-
tients on surveillance includes abdominopelvic
CT every 3–4 months in the first year, every
4–6 months in the second year, every 6–12
months in the third and fourth years, every 12
months for the fifth year, and then every 12–24
months for the sixth year and beyond. Howev-
er, the frequency of repeat CT is a subject of
much controversy and research due to the con-
cern of radiation exposure and secondary ma-
lignancies, especially in younger patients [46].
A
Fig. 7—59-year-old man who presented with sudden onset of abdominal pain and vomiting.
A, Abdominal CT image shows large interaortocaval mass. Physical examination revealed indurated right testicle. Subsequent testicular ultrasound revealed 3-cm
intratesticular mass, which was found to be seminoma. Patient subsequently underwent four cycles of etoposide and cisplatin (EP) chemotherapy.
B, Abdominal CT image obtained after chemotherapy shows residual interaortocaval mass, which may be necrosis, teratoma, or persistent malignancy.
B
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7. AJR:200, June 2013 1221
Imaging Testicular Cancer
Radiation-Induced Secondary
Malignancies
Although there are minimal large-scale epi-
demiologic studies of the cancer risk associ-
ated with CT, there is evidence from atom-
ic bomb survivor studies that suggests an
increased risk of radiation-induced cancers
with exposure equivalent to 2–3 abdominal
CT studies (dose in the range of 30–90 mSv)
[47, 48]. A recent study examined the risk of
secondary malignancies in testicular cancer
patients subjected to a median of 10 CT stud-
ies over a 5-year period with a median radia-
tion exposure of 110 mSv and found that sec-
ondary malignancies of the abdomen-pelvis
were uncommon in men with testicular cancer
and that radiation exposure was not associated
with an excess risk of secondary cancers [49].
It stands to reason that the dose of radia-
tion should be as low as reasonably achiev-
able (ALARA principle) as evidenced by the
decreasing number of follow-up CT studies
recommended by contemporary guidelines.
In addition, a trial is currently under way in
the United Kingdom (Trial of Imaging and
Schedule in Seminoma Testis [TRISST]) to
determine whether MRI studies are as ef-
fective as CT studies in detecting relapse
of testicular cancer. Further dose reduction
strategies, including low-dose protocols, us-
ing chest CT only when indicated, limiting
the region scanned, and using MRI when-
ever possible, should be incorporated into
the management of testicular cancer patients
[47, 50].
Imaging Modalities for Assessing
Residual or Recurrent Disease
CT remains the standard imaging mo-
dality for assessing response to treatment
and to identify recurrent disease during fol-
low-up. For those patients who had a com-
plete response to chemotherapy, six CT stud-
ies are recommended over the first 5 years
[42] (Fig. 7). It is important to note that af-
ter chemotherapy for retroperitoneal disease
in NSGCT, any visible residual adenopathy
should be reported because even small re-
sidual nodes can harbor viable microscopic
disease. For patients who had RPLND as the
primary treatment of stage I or II disease, a
baseline postoperative CT study is recom-
mended, with additional CT as clinically in-
dicated [42].
The FDG-PET in Seminoma-Residu-
als (SEMPET) trial confirmed the utility of
FDG PET in detecting postchemotherapy
residual retroperitoneal disease in patients
with seminoma [51]. This remains the only
indication for FDG PET in the NCCN guide-
lines because of a paucity of evidence sup-
porting its use in other situations [42].
Novel Imaging Techniques in
Testicular Cancer
A number of novel imaging techniques
that can be used in the diagnosis, staging, and
follow-up of testicular cancer are in various
stages of investigation.
A
D
Fig. 8—Lymphotrophic nanoparticle–enhanced MRI. (Reprinted with permission from [52])
A–C, 48-year-old man with benign interaortocaval node. Axial contrast-enhanced CT image (A) shows 1-cm node (arrow) in interaortocaval region. Unenhanced MR
image (B) shows homogeneous high signal intensity of node (arrow). Lymphotrophic nanoparticle–enhanced MR image shows homogeneous darkening of lymph node
(arrow), indicative of benign cause for enlargement.
D–F, 21-year-old man with malignant interaortocaval lymph node (arrow). Axial contrast-enhanced CT image (D) shows 1-cm node in interaortocaval region. Unenhanced
MR image shows homogeneous high signal intensity of node. Lymphotrophic nanoparticle–enhanced MR image shows darkening in posterior aspect of node with
heterogeneity in anterior node. Heterogeneity is indicative of malignant infiltration.
C
F
B
E
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8. 1222 AJR:200, June 2013
Kreydin et al.
Lymphotrophic Nanoparticle–Enhanced MRI
Lymphotrophic nanoparticle–enhanced MRI
relies on a new class of MRI contrast agents
with unique biochemical properties [52]. These
contrast agents are composed of superparamag-
netic iron oxide nanoparticles that are small
enough to pass freely from the venous sys-
tem into the medullary sinuses of lymph nodes
where they are phagocytosed by macrophages
of the reticuloendothelial system [53]. Whereas
benign lymph nodes have normally functioning
macrophages that avidly take up these particles,
macrophages in lymph nodes infiltrated with
tumor have dysfunctional phagocytosis. The
disparity in nanoparticle take-up results in dif-
ferential enhancement of benign and malignant
lymph nodes on MRI (Fig. 8).
Lymphotrophic nanoparticle–enhanced MRI
was originally used in urologic practice for en-
hanceddetectionof inguinallymphnodemetas-
tases in penile cancer [54]. The efficacy of this
modality in testicular cancer was first investi-
gated in a 2005 pilot study. This study com-
pared the sensitivity and specificity of lym-
photrophic nanoparticle–enhanced MRI and
abdominal CT with a reference standard (per-
cutaneous or laparoscopic biopsy of retroperi-
toneal lymph nodes) in 18 patients with known
seminomatous and nonseminomatous GCTs
[54]. Lymphotrophic nanoparticle–enhanced
MRI was found to be more sensitive (88% vs
70%) and specific (92% vs 68%) than abdom-
inal CT in identifying positive lymph nodes.
Although lymphotrophic nanoparticle–en-
hanced MRI appears to be a promising tech-
nique, it requires significant expertise in MRI
interpretation. Furthermore, imaging must oc-
cur 24–36 hours after contrast administration
because of the specific bioavailability prop-
erties of the nanoparticles [53]. Individual
nodes are typically compared with each other
in separate scans before and after contrast ad-
ministration [55]; however, it has been shown
that a single-scan evaluation is feasible with
no loss in efficacy [56]. A recent meta-anal-
ysis confirmed that lymphotrophic nanoparti-
cle–enhanced MRI offers an improved means
of lymph node staging in genitourinary malig-
nancy [57]. Therefore, further investigation of
this technique in staging of testicular cancer
appears warranted.
PET/CT Imaging
A study published in 2010 assessed the ef-
ficacy of PET/CT fusion imaging to detect tes-
ticular cancer metastases in a series of 49 pa-
tients [58] (Fig. 9). These authors found that
the sensitivity and specificity of PET/CT were
superior to either study alone in identifying
and following metastatic disease. Although
differentiation between teratoma and fibrosis
or necrosis could not be achieved using PET/
CT (as with other commonly used nuclear im-
aging modalities), detection and localization
of micrometastatic disease, which would oth-
erwise be missed on CT, were improved.
As discussed previously, nuclear imaging
has found an application in staging of semi-
nomatous GSTs, especially in the postchemo-
therapy setting. However, the use of PET for
posttreatment staging in cases of nonsemino-
matous GSTs has proven difficult because
FDG uptake of mature teratoma is similar to
that of necrotic and fibrotic masses. A number
of approaches have been developed to circum-
vent this obstacle.
The use of dynamic FDG scanning, which
evaluates the kinetic rate constants of FDG
uptake, was first evaluated in a 1999 study by
Sugawara et al. [59]. In particular, these au-
thors evaluated various parameters of FDG
uptake kinetics (transfer from bloodstream to
tissue [k1], phosphorylation [k2], and transfer
from tissue back to the bloodstream [k3]) and
found that k1 was significantly elevated in ma-
ture teratoma compared with necrotic tissue.
These findings led to the suggestion that pa-
tients with NSGCT who have a negative PET
and a low k1 could be observed, whereas those
with a negative PET and an elevated k1 should
undergo resection for presumed teratoma. Be-
cause it is difficult to implement dynamic
FDG scanning in clinical practice because of
its time-consuming nature, to our knowledge,
this concept has not been tested in any addi-
tional clinical studies.
PET tracers (e.g., L-C-11 tyrosine) that are
preferentially taken up by cells with increased
amino acid metabolism have been evaluated in
identifying NSGCT metastases. Unfortunate-
ly, initial studies have shown that these mark-
ers are not helpful in identifying metastases
because of the relatively slow proliferation of
teratoma cells [60]. Similar results were ob-
tained with radioactive thymidine (a DNA nu-
cleoside). Although both FDG and 18F-FDT
were able to detect testicular tumor metastases
in agreement with CT, neither could faithfully
identify mature teratoma [61].
A novel tracer has shown some success in
both identifying NSGCT metastases and dif-
A
Fig. 9—32-year-old man with mixed nonseminomatous giant cell tumor (NSGCT) for NSGCT. Functional imaging, such as 18F-FDG PET/CT fusion, may offer
improved ability to detect lymph node metastases in testicular cancer. Original figure from Sterbis JR, Rice KR, Javitt MC, Schenkman NS, Brassell SA. Fusion
imaging: a novel staging modality in testis cancer. J Cancer 2010; 1:223–229
A, Abdominal CT image obtained in patient with mixed NSGCT does not reveal any pathologic lymphadenopathy.
B, Fusion PET/CT obtained in same patient shows increased uptake in retroperitoneal lymph node. Patient subsequently underwent retroperitoneal lymph node
dissection, which revealed embryonal and teratoma metastases on pathologic examination.
B
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9. AJR:200, June 2013 1223
Imaging Testicular Cancer
ferentiating retroperitoneal necrosis from ter-
atoma after chemotherapy because many
tumors, including teratoma, express αVβ3 in-
tegrin on their cell surface. This integrin is
thought to mediate angiogenesis and plays a
critical role in growth and metastasis of ovar-
ian cancer [62]. The αVβ3 integrin recognizes
ligands that possess the arginine-glycine-as-
partic acid (RDG) amino acid sequence and
shows promise for preventing unnecessary
surgical exploration in postchemotherapy. In
a 2011 study, Aide et al. [62] used a radiola-
belled RGD tracer to identify mature teratoma
in a rat model of NSGCT treated with cispla-
tin and to differentiate it from necrotic lesions
[62]. Their findings were confirmed in at least
one more study that showed RGD tracer up-
take in mature teratoma cells in vitro [63]. Al-
though RGD imaging has not been performed
in human subjects yet, it appears to be a prom-
ising novel modality to prevent unnecessary
surgical exploration in patients with NSGCT
who have undergone chemotherapy.
Summary
Imaging studies play a vital role in the di-
agnosis and management of testicular can-
cer. Ultrasound is primarily used for initial
diagnosis, and CT is the standard for cancer
staging. MRI provides an equally powerful
diagnostic alternative to CT for use in cer-
tain circumstances. The use of PET is lim-
ited in tumor characterization, but, with the
advent of new tracers, PET is gaining ac-
ceptance for the evaluation of treatment re-
sponse as well as recurrence.
Acknowledgment
We would like to thank Mukesh Harisinghani
for his assistance with editing and obtaining
images for this manuscript.
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(Appendix appears on next page)
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11. AJR:200, June 2013 1225
Imaging Testicular Cancer
APPENDIX 1: Testicular Cancer TNM (2010) Staging System [21]
Primary tumor (T)—The extent of the primary tumor is usually classified after radical orchiectomy, and for this reason,
a pathologic category is assigned.
pTx Primary tumor cannot be assessed
pT0 No evidence of primary tumor (e.g., histologic scar in testis)
pTis Intratubular germ cell neoplasia (carcinoma in situ)
pT1 Tumor limited to the testis and epididymis without vascular or lymphatic invasion; tumor may invade into the tunica albuginea
but not the tunica vaginalis
pT2 Tumor limited to the testis and epididymis with vascular or lymphatic invasion, or tumor extending through the tunica albuginea
with involvement of the tunica vaginalis
pT3 Tumor invades the spermatic cord with or without vascular or lymphatic invasion
pT4 Tumor invades scrotum with or without vascular or lymphatic invasion
Regional lymph nodes (N)—Clinical category
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis with a lymph node mass 2 cm or less in greatest dimension or multiple lymph nodes, none more than 2 cm in greatest
dimension
N2 Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension or multiple lymph nodes, any
one mass greater than 2 cm but not more than 5 cm in greatest dimension
N3 Metastasis with a lymph node mass more than 5 cm in greatest dimension
Regional lymph nodes (N)—Pathologic category
pNx Regional lymph nodes cannot be assessed
pN0 No regional lymph node metastasis
pN1 Metastasis with a lymph node mass 2 cm or less in greatest dimension and five or fewer nodes positive, none more than 2 cm in
greatest dimension
pN2 Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; more than five nodes positive,
none more than 5 cm; or evidence of extranodal extension of tumor
pN3 Metastasis with a lymph node mass more than 5 cm in greatest dimension
Distant metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
M1a Nonregional nodal or pulmonary metastasis
M1b Distant metastasis other than to nonregional nodes and lungs
Serum tumor markers (S)—S category is determined using the nadir value of the postorchiectomy tumor markers.
Sx Tumor marker studies not available or not performed
S0 Tumor marker levels within normal limits
S1 Lactate dehydrogenase (LDH) < 1.5 times normal and HCG < 5000 mIU/mL and α-fetoprotein (AFP) < 1000 g/mL
S2 LDH 1.5–10 times normal or HCG 5000–50,000 mIU/mL or AFP 1000–10,000 g/mL
S3 LDH > 10 times normal or HCG > 50,000 mIU/mL or AFP > 10,000 g/mL
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