The n e w e ng l a n d j o u r na l
case records of the massachusetts general hospital
From the Departments of Hematology–
Oncology (D.S.K.), Radiology (M.A.S.),
Pathology (R.H.Y.), and Urology (S.T.),
Massachusetts General Hospital; and the
Departments of Medicine (D.S.K.), Radi-
ology (M.A.S.), Pathology (R.H.Y.), and
Urology (S.T.), Harvard Medical School.
N Engl J Med 2007;356:842-9.
Copyright © 2007 Massachusetts Medical Society.
842
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of m e dic i n e
Founded by Richard C. Cabot
Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor
Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor
Case 6-2007: A 28-Year-Old Man
with a Mass in the Testis
Donald S. Kaufman, M.D., Mansi A. Saksena, M.D., Robert H. Young, M.D.,
and Shahin Tabatabaei, M.D.
Pr e sen tat ion of C a se
A 28-year-old man was referred to this hospital for consultation on the management
of an enlarging testicular mass.
One year earlier, he had noticed a small, nontender mass in the posterior aspect
of the right testicle, which a physician, who was a relative of the patient, ascribed to
epididymitis; the mass seemed to disappear, or at least the patient did not notice it
again. One month before the consultation, the results of a routine annual physical
examination were normal; no abnormalities were noted in the testicles. Ten days
before the consultation, the right testicle became tender and began to enlarge
rapidly. The patient did not have fever or constitutional symptoms. His primary care
physician began treatment with levofloxacin. The results of laboratory studies —
including urinalysis, complete blood count, platelet count, erythrocyte sedimentation
rate, and liver-, renal-, and thyroid-function tests — were normal.
The testicular tenderness decreased, but the swelling persisted. One week later,
an ultrasound examination performed at another hospital showed a complex testic­
ular mass that was considered highly suggestive of cancer. The patient’s physician
recommended an immediate biopsy of the testis, but the patient decided to come
to this hospital for a second opinion.
He felt well and had no constitutional, gastrointestinal, or urinary symptoms. He
had been in excellent health, had no allergies, and took no medications. He had
never had a urinary tract infection or epididymitis, and there was no history of in-
guinal hernia or sexually transmitted disease. He had never smoked; he occasional­ly
drank alcohol. He had married 4 months earlier and had no children. A grandfather
had died of pancreatic cancer, and a grandmother had cancer, but the patient did
not know the primary site. There was no family history of testicular or other geni-
tourinary cancer.
On physical examination, the patient appeared well, although anxious. His vital
signs and the results of the general physical examination were normal; there was
no tenderness of the breasts or gynecomastia. The left testis was normal; the right
testis contained a firm, nontender mass, 4 cm in diameter. The epididymis was
normal. A specimen of blood was drawn to test for tumor markers.
n engl j med 356;8  www.nejm.org  february 22, 2007
 case records of the massachuset ts gener al hospital

Later that day, a diagnostic procedure was per-

formed. A

Differ en t i a l Di agnosis

Dr. Donald S. Kaufman: Dr. Saksena, will you review

the ultrasound study?
Dr. Mansi A. Saksena: The testicular ultrasound
study performed at the other hospital showed a
complex intratesticular mass, 3.1 by 2.9 cm, with
mixed cystic and solid components, within an en­
larged right testis (Fig. 1). A Doppler study showed
minimal vascularity within the solid components
of the mass. The right epididymis and the left
testis and epididymis were normal.
Because the mass was intratesticular, the diag-
nosis of a hernia, varicocele, or scrotal hematoma
could be ruled out. Since the lesion was well de-
fined, with normal adjacent testicular parenchy-
ma, testicular torsion was unlikely. The age of the
patient and the ultrasonographic appearance of B
the mass suggest that it is a testicular neoplasm.1
Dr. Kaufman: Dr. Tabatabaei, would you discuss
the differential diagnosis of a testicular mass
presenting as it did in this young man?
Dr. Shahin Tabatabaei: The patient presented to
his primary care physician with the relatively
abrupt onset of testicular pain and swelling and
a mass in the scrotum. Important factors to con-
sider in formulating a differential diagnosis in-
clude the patient’s age; the rapidity of the onset
of symptoms; the presence or absence of pain,
fever, and local tenderness; and the results of the
physical examination. Scrotal masses may be due
to neoplasia, inflammation, or anatomical defects.
The differential diagnosis of a scrotal mass in a
young man such as this one includes testicular
Figure 1. Ultrasonographic Images of the Right Testis.
cancer, hydrocele, spermatocele, inguinal hernia,
A transverse image through the right testicle (Panel A)
epididymo-orchitis, trauma, and epidermoid cyst. shows a complex intratesticular mass with a cystic
Although benign scrotal masses are more com- component
ICM AUTHOR Kaufman
(arrowhead) and a solid component
RETAKE (arrow).
1st

mon than malignant ones, it is crucial to rule out Normal

REG Ftesticular
FIGURE tissue
1a&b is
of seen
2 2nd
along the anterior aspect
3rd
CASE
of the mass. A Doppler image (Panel B) reveals minimal
the possibility of malignant causes before consid- EMail
TITLE Revised
vascularity in the solid component
Line (arrow).
4-C
ering conservative management. Enon ARTIST: mst SIZE
H/T H/T
Most inflammatory scrotal masses are associ- FILL Combo 16p6
ated with scrotal pain, whereas noninflammatory AUTHOR, PLEASE NOTE:
conditions, including testicular cancer, are more patient,Figure
doeshasnot
been redrawn and type has been reset.
rule check
Please out the diagnosis of testicu-
carefully.
often painless. However, acute pain occurs in lar cancer.
about 10% of patients with testicular tumors, The
JOB:most
35608common inflammatory cause of a
ISSUE: 2-22-07
usually because of bleeding inside the tumor scrotal mass is epididymitis or epididymo-orchi-
or associated epididymitis that can cause acute tis. This patient had noted a mass a year earlier
swelling and pain. Therefore, an acute presenta- that was thought to be epididymitis. Considering
tion of testicular swelling and pain, as in this the relatively rapid growth of testicular germ-cell

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 The n e w e ng l a n d j o u r na l
tumors (doubling time of 10 to 30 days), it is un-
likely that this mass was the initial manifestation
of a testicular cancer. Epididymo-orchitis is often
associated with systemic symptoms such as fever
and fatigue, as well as urinary symptoms, which
were not present in this patient. In rare cases,
sarcoidosis is manifested as a scrotal mass, but
the process is usually bilateral.
The clinical history is important, since condi-
tions such as hydrocele and hernia often develop
gradually and are chronic, whereas a sudden on-
set would be more characteristic of infection or
torsion. Also important is a history of trauma,
which was not present in this case.
On physical examination, a hydrocele, sperma­
tocele, or hernia would be fluctuant rather than
firm. Transillumination may help to differentiate
hernia from spermatocele or hydrocele. Epider-
moid cysts are fixed to the skin. The presence of
localized tenderness of the epididymis, with or
without diffuse testicular swelling and tender-
ness, would suggest epididymitis or epididymo-
orchitis. Testicular cancers usually form a discrete,
firm, nontender mass within the testis; however,
the entire testis may be enlarged and, as in this
case, painful. A firm, nontender testicular mass
in a patient between the ages of 18 and 45 years
should be presumed to be malignant until proved
otherwise. In cases, such as this one, that pre­
sent initially with diffuse testicular pain and swell-
ing, the distinction between cancer and infection
may be difficult to make. In such a case, I feel
strongly that an immediate testicular ultrasound
study should be the next step. Although this ex-
amination may not be required in cases in which
the history and findings on physical examination
are typical, it can confirm the diagnosis in diffi-
cult cases and allows one to proceed with treat-
ment right away. A trial of antibiotics, which is
often undertaken, as it was in this case, can lead
to an unacceptable delay in the diagnosis, espe-
cially if the patient is not compliant with follow-
up. A delayed diagnosis of testicular cancer can
be associated with the finding of a later stage of
the disease at the time of diagnosis, and it may
affect the chance of cure.2,3 Reevaluation by the
patient’s physician 1 week later showed a persis-
tent nontender mass. At this point, an ultrasound
examination was performed.
Dr. Kaufman: This patient’s physician advised a
testicular biopsy for diagnosis. The patient came
to see me 2 days later for a second opinion. Since
844 n engl j med 356;8  www.nejm.org  february 22, 2007
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of m e dic i n e
testicular cancer seemed the most likely clinical
diagnosis, I recommended immediate radical or-
chiectomy, the procedure of choice for a suspected
testicular cancer. Blood was drawn for assessment
of tumor markers, the beta subunit of human
chorionic gonadotropin, and alpha-fetoprotein,
and the patient saw Dr. Tabatabaei later that day.
Dr. Tabatabaei: Testicular cancer is usually a
clinical diagnosis. The use of scrotal ultrasound
is merely confirmatory. This patient’s presentation
was very characteristic of a neoplastic process, so
Dr. Kaufman and I saw no need to wait for a
computed tomographic (CT) scan or for the re-
sults of tumor markers. Later that day, I performed
a right radical orchiectomy.
Pathol o gic a l Dis cus sion
Dr. Robert H. Young: The specimen was received for
intraoperative consultation. The testis contained
a mass that was obvious on palpation; sectioning
revealed a mass 4 cm in diameter with a varie-
gated appearance, including yellow-to-white solid
areas, focal hemorrhage, and minor cystic areas
(Fig. 2A). The most likely diagnosis of a mass with
this appearance, particularly at this patient’s age,
is either pure embryonal carcinoma or a mixed
germ-cell tumor, which often has a component
of embryonal carcinoma. Seminoma is usually a
more uniform, creamy white neoplasm, although
it can exhibit hemorrhage or necrosis.4
On microscopical examination, the tumor was
largely an embryonal carcinoma, which is a prim­
itive adenocarcinoma of the testis with papillary
(Fig. 2B), glandular, and solid patterns. The tumor
cells were highly malignant in appearance, with
pleomorphism and prominent nucleoli (Fig. 2C).
The papillary and overt glandular pattern rules
out a diagnosis of seminoma. There were minor
foci of yolk-sac tumor with a microcystic pattern
and teratomatous foci (Fig. 2D). Seminomas may
occasionally form spaces,5 but the appearance is
different from that of embryonal carcinomas. A
distinction between seminoma and embryonal
carcinoma can usually be made by evaluating
slides obtained routinely and stained with hema-
toxylin and eosin, but if indicated, immunohisto-
chemistry may aid in the distinction, since em-
bryonal carcinoma is negative for c-kit (CD117)
and positive for CD30, unlike seminoma.6
The tumor also had syncytiotrophoblastic giant
cells, which are common in embryonal carcinoma
 case records of the massachuset ts gener al hospital

A B

C D

Figure 2. Gross and Microscopical Features of the Testicular Tumor.

The sectioned surface of the testicular tumor shows mostly solid, yellow-to-white tissue, with focal hemorrhage and
a few cysts (Panel A). The tumor has the typical papillary (Panel B, hematoxylin and eosin) and glandular pattern of
embryonal carcinoma. A high-powerICM AUTHOR
view (Panel Kaufman
C, hematoxylin and eosin)RETAKE
shows the 1stpleomorphic nuclei and dusky
F FIGURE 2a-d of 2 A teratomatous component 2nd
cytoplasm that are characteristic ofREG
embryonal carcinoma. (Panel D, hematoxylin and
CASE 3rd
eosin) has squamous epithelium with keratin production (left) and teratomatous
TITLE Revised glands (right).
EMail Line 4-C
Enon ARTIST: mst SIZE
H/T H/T
and sometimes lead to a misdiagnosis
FILL of chorio- mor markers, 33p9
Combo and chest and abdominopelvic CT
carcinoma. Many testicular tumors with AUTHOR, a com- PLEASE
studies.
NOTE:Dr. Saksena, will you describe the find-
Figure has been redrawn and type has been reset.
ponent of embryonal carcinoma have at least Please a ings
check on the postoperative abdominopelvic and
carefully.
minor teratomatous component. This very com- chest CT scans?
mon mixture of embryonal carcinomaJOB: 35608 and tera- Dr.ISSUE: 2-22-07
Saksena: Contrast-enhanced CT scanning of
toma was called teratocarcinoma in the older the abdomen, pelvis, and chest was performed
literature. the day after surgery. There were no lung nodules
On microscopical examination, the tumor, or lymphadenopathy in the mediastinum, retro-
about 60% of which was embryonal carcinoma, peritoneum, or pelvis.
was shown to be confined to the testis, without Dr. Kaufman: Germ-cell tumors of the testis
any penetration of the tunica albuginea. There are uncommon but not rare. The usual age at the
was very focal vascular invasion. time of diagnosis is 18 to 40 years, and these
tumors are the most common solid neoplasms in
Dis cus sion of M a nage men t men between the ages of 20 and 34 years. There
are several histologic types of germ-cell tumors
Dr. Kaufman: In this case, the essential procedures and combinations thereof (Table 1). The Interna-
and tests for the clinical and pathological diag- tional Germ Cell Cancer Collaborative Group7
nosis and staging of a germ-cell tumor of the lists three prognostic categories — good, inter-
testis included radical orchiectomy, tests for tu- mediate, and poor (Table 2) — based on a com-

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 The n e w e ng l a n d j o u r na l
bination of histologic features, site at presenta-
tion, stage, and tumor markers.
Testicular Cancer Staging
In addition to the tumor–node–metastasis stag-
ing system for testicular neoplasms, the current
system includes a category for tumor markers
(Table 3).8 In this patient, the serum level of beta
human chorionic gonadotropin was 16 mIU per
milliliter (normal value, less than 5), and the
alpha-fetoprotein level was 10.5 ng per milliliter
(normal value, less than 6.1). The lactate dehydro-
genase level was normal. On the basis of the size
of the tumor and the levels of tumor markers, the
tumor is stage IA, which falls into the good
prognostic group.
Treatment of Early-Stage, Nonseminomatous
Germ-Cell Tumors
Currently, there is controversy regarding the opti-
mal treatment of stages IA, IB, and IIA testicular
cancers. It is generally agreed that stage IIB tumors
should be managed, at least initially, with chemo-
therapy. Radiation therapy, the treatment of choice
for patients with stage I seminoma, is not used in
the initial management of early-stage, nonsemi-
nomatous germ-cell tumors. Thus, the three adju-
vant treatment options for this patient are active
surveillance, primary retroperitoneal lymph-node
dissection, and chemotherapy. All options result
in cure rates of 99% in cases such as this one, but
two thirds of patients are already cured after or-
chiectomy. Since all adjuvant treatments are as-
sociated with side effects, the goal is to provide
tailored adjuvant treatment for patients at high
risk for relapse and to avoid adjuvant treatment
for those at low risk for relapse.
Active Surveillance
Because patients with clinical stage I germ-cell
tumors have a 5-year survival rate that approach-
es 100%, some investigators have tried to reduce
the short-term and long-term toxicity of therapy,
including the elimination of a routine staging
retroperitoneal lymph-node dissection for select-
ed patients. Surveillance (i.e., observation alone
after radical orchiectomy) is safe if the schedule
of laboratory tests, radiologic studies, and visits
to the physician is followed precisely. Although
the relapse rate is 20 to 30% among all patients
with clinical stage I, nonseminomatous germ-cell
tumors, more than 98% of these patients’ cancers
846 n engl j med 356;8  www.nejm.org  february 22, 2007
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of m e dic i n e
Table 1. Germ-Cell Tumors of the Testis in Adults.*
Approximate
Tumor Type Frequency
%
Seminoma 50
Nonseminomatous germ-cell tumor 50
Pure nonseminomatous germ-cell tumor 15
Embryonal carcinoma 10
Choriocarcinoma <1
Teratoma 3–5
Yolk-sac tumor <1
Mixed nonseminomatous germ-cell tumor 35
Embryonal plus other types 20
* Data are from Ulbright et al.4 Percentages in subcategories
are for the overall category.
are eventually cured.9 The advantage of surveil-
lance is that at least 70% of patients do not need
any treatment after orchiectomy. One disadvan-
tage is that up to 30% of patients must eventually
undergo four or more cycles of chemotherapy,
with the associated side effects. Furthermore, the
strict follow-up schedule may induce stress and
invite noncompliance.
Active surveillance protocols vary among insti-
tutions,10,11 but they typically include monthly
measurement of serum tumor markers and reg-
ular imaging studies for 2 years; I recommend
CT scanning of the chest and abdomen every
3 months. Since most relapses in patients with
nonseminomatous germ-cell tumors occur within
the first 2 years and are rare after 5 years, annual
surveillance is recommended after 5 years.
The patient under discussion is an excellent
candidate for active surveillance. His tumor mark-
ers fell to undetectable levels after orchiectomy,
his CT scan was normal, and compliance was
clearly not going to be a problem in obtaining the
necessary blood tests for tumor markers, chest
radiographs, and abdominal CT scans for the
duration of surveillance.9
Primary Retroperitoneal Lymph-Node Dissection
Among patients with stage I, nonseminomatous
germ-cell tumors who have no evidence of in-
volvement of retroperitoneal lymph nodes on im-
aging studies, subsequent lymph-node dissection
shows positive nodes in about 30%. This proce-
dure is an attractive alternative for patients who
may not be fully compliant with surveillance or
 case records of the massachuset ts gener al hospital

Table 2. Prognostic Factors and Survival among Patients with Nonseminomatous Testicular Germ-Cell Tumors.*

Good prognosis (56% of nonseminomatous germ-cell tumors)

Prognostic factors: testicular or retroperitoneal primary tumor, no nonpulmonary visceral metastasis, and low levels
of tumor markers (alpha-fetoprotein <1000 ng/ml, beta human chorionic gonadotropin <5000 IU/liter, and lactate
dehydrogenase <1.5 times ULN)
5-Year survival rate: progression-free, 89%; overall, 92%
Intermediate prognosis (28% of nonseminomatous germ-cell tumors)
Prognostic factors: testicular or retroperitoneal primary tumor, no nonpulmonary visceral metastases, and intermediate
levels of tumor markers (alpha-fetoprotein ≥1000 and ≤10,000 ng/ml, beta human chorionic gonadotropin ≥5000
and ≤50,000 IU/liter, lactate dehydrogenase ≥1.5 times and ≤10 times ULN)
5-Year survival rate: progression-free, 75%; overall, 80%
Poor prognosis (16% of nonseminomatous germ-cell tumors)
Prognostic factors: mediastinal primary tumor, nonpulmonary visceral metastasis, or high level of a tumor marker
(alpha-fetoprotein >10,000 ng/ml, beta human chorionic gonadotropin >50,000 IU per liter, or lactate dehydrogenase
>10 times ULN)
5-Year survival rate: progression-free, 41%; overall, 48%

* ULN denotes the upper limit of the normal range.

who would have difficulty with observation be- primary systemic chemotherapy as a means of
cause their awareness that the surveillance ap- circumventing both retroperitoneal lymph-node
proach carries a 30% risk of relapse and that a dissection and active surveillance. For patients
relapse would require chemotherapy makes this with disease that is stage IIB or higher and for
an unacceptable alternative. In a retrospective those with elevated tumor markers after orchiec-
comparison of retroperitoneal lymph-node dissec- tomy, chemotherapy is the treatment of choice.
tion and surveillance for patients with clinical Cisplatin-based chemotherapy, a mainstay in
stage I disease, the disease-specific survival ratethe primary treatment of germ-cell neoplasms of
was greater than 98% for both options.12 the testis, is associated with complications that
A later clinical stage and the presence of per-include Raynaud’s phenomenon,14 peripheral neu-
sistently elevated serum tumor markers after or- ropathy,15 nephropathy, and secondary leukemia.16
chiectomy are independent predictors of progres- Most important, a number of studies have shown
sion. In a study of patients with clinical stage I an increased risk of cardiovascular disease among
to IIA disease and normal marker levels after long-term survivors of testicular germ-cell tumors
orchiectomy, the 4-year progression-free survival treated with cisplatin.17-22 Patients with testicular
rate after retroperitoneal lymph-node dissection cancer are typically young at the time of treat-
was 96%.13 This procedure represents an accept- ment and usually survive for many years. Thus,
able option for primary intervention in stages I the potential for serious late cardiovascular dis-
and IIA testicular germ-cell tumors. It is not in­ ease needs to be considered when deciding wheth-
dicated if tumor markers remain elevated after er to use chemotherapy for testicular cancer and
the orchiectomy or if the clinical stage is IIB or when following patients who have received che-
higher. motherapy in the past.23
Retroperitoneal lymph-node dissection carries Because this patient’s tumor falls into a good
a small risk of complications that can occur with prognostic category and because of the risks as-
any major abdominal operation. In particular, this sociated with chemotherapy, I did not recommend
procedure confers a risk of retrograde ejaculation chemotherapy as an option.
and subsequent infertility (a risk that can be re- Dr. Tabatabaei, would you advise doing a retro­
duced with nerve-sparing dissection) and small- peritoneal lymph-node dissection in this case?
bowel obstruction due to adhesions. Dr. Tabatabaei: The patient has clinical stage I
disease. Approximately 60% of his tumor was
Chemotherapy embryonal carcinoma, and lymphovascular inva-
A third alternative for patients with early-stage sion was only focally present. Although stage I,
disease is a short course (one to three cycles) of nonseminomatous germ-cell tumors that are more

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 The n e w e ng l a n d j o u r na l of m e dic i n e

undetectable 2 weeks after the orchiectomy. The

Table 3. Staging System for Early-Stage Testicular Germ-Cell Tumors.*
patient is therefore a good candidate for surveil-
Stage Tumor† Node‡ Metastasis§ Serum Tumor Markers¶ lance; chemotherapy can be used if he has a re-
IA T1 N0 M0 S0 lapse. I would recommend retroperitoneal lymph-
IB T2–T4 N0 M0 S0 node dissection only if the tumor relapses and if
IIA T2–T4 N1 M0 S0–1
there are residual tumor masses after chemo-
therapy for relapsed disease.
IIB T2–T4 N2 M0 S0–1
Dr. Kaufman: We discussed the advantages and
disadvantages of retroperitoneal lymph-node dis-
* Data are from Greene et al.8 Tumor stages are classified according to the cri-
teria of the American Joint Committee on Cancer. section with the patient, but for a stage I tumor,
† T1 indicates that the tumor is limited to the testis, without vascular invasion; we preferred active surveillance, as did the pa-
T2–T4 indicates vascular invasion and involvement of the tunica vaginalis, tient. He was emphatically opposed to undergo-
spermatic cord, or scrotum.
‡ N0 indicates no evidence of a tumor in the lymph nodes; N1 a lymph-node ing retroperitoneal lymph-node dissection and
mass 2 cm or less in diameter or up to five positive nodes, each 2 cm or less highly committed to the strict regimen of follow-
in diameter; and N2 a lymph-node mass more than 2 cm but not more than up required for active surveillance. He is being
5 cm in diameter, or more than 5 positive nodes with none more than 5 cm
in diameter, or evidence of extranodal extension of tumor. followed at a cancer center in his home state,
§ M0 denotes no distant metastases. with monthly assessment of tumor markers and
¶ S0 denotes normal levels of alpha-fetoprotein, beta human chorionic gonado- monthly chest radiographs. Eighteen months af-
tropin, and lactate dehydrogenase, and S1 the following levels: alpha-fetopro-
tein, less than 1000 ng per milliliter; beta human chorionic gonadotropin, less ter the operation, he is well, with no evidence of
than 5000 mIU per milliliter; and lactate dehydrogenase, less than 1.5 times recurrence.
the upper limit of the normal range.

A nat omic a l Di agnosis

than 50% embryonal carcinoma and those with
lymphovascular invasion have each been reported Mixed germ-cell tumor (embryonal carcinoma,
to be associated with an increased risk of re- teratoma, and scant yolk-sac tumor).
lapse,10 in this case, the vascular invasion was No potential conflict of interest relevant to this article was re-
minimal, and the levels of tumor markers were ported.

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