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337
Sarcoidosis and Testicular Carcinoma
Daniel Rayson, M.D.
Patrick A. Burch, M.D.
Ronald L. Richardson,
M.D.
Division of Medical Oncology, Mayo Clinic and
Mayo Foundation, Rochester, Minnesota.
BACKGROUND. Case reports and small case series have described patients with
sarcoidosis and testicular carcinoma. The goals of this study were to determine the
incidence of sarcoidosis in patients with testicular carcinoma seen at the Mayo
Clinic between 1950 and 1996 and to examine the relation between these two
diseases, particularly in regard to the therapy and follow-up of patients with
testicular carcinoma.
METHODS. A computerized search of the patient data base at the Mayo Clinic was
conducted to identify all patients seen between 1950 and 1996 who had a diagnosis
of a malignant testicular tumor and sarcoidosis.
RESULTS. A total of 14 patients were identified. The median age at diagnosis of
testicular carcinoma was 31.5 years. Eleven patients presented with Stage I disease
and 3 with Stage II disease. Twelve patients had carcinoma diagnosed before
sarcoidosis. The median age at the time of diagnosis of sarcoidosis was 36.5 years.
Nine patients presented with radiographic Stage I disease, four with radiographic
Stage II disease, and one with extrapulmonary disease. The estimated cumulative
incidence of sarcoidosis in patients with testicular carcinoma seen at the Mayo
Clinic between 1976 and 1995 was 617.3 per 100,000.
CONCLUSIONS. These data suggest that, compared with other solid tumors, testicular carcinoma has the strongest association with sarcoidosis. The observed incidence represents an approximate 100-fold increase compared with a general
population of young white men. Although an etiologic relation is possible, the
problems of access and surveillance bias should be addressed in prospective
studies. Cancer 1998;83:337– 43. © 1998 American Cancer Society.
KEYWORDS: epidemiology, sarcoidosis, testicular carcinoma, incidence, association.
Presented in part at the 66th Annual Meeting of the
Royal College of Physicians and Surgeons of Canada (RCPSC), Vancouver, British Columbia, Canada, September 24-28, 1997.
The authors thank J. P. Utz, M.D., Division of
Pulmonary and Critical Care Medicine and Internal
Medicine, and S. J. Jacobsen, M.D., Section of
Clinical Epidemiology, for their review of the article.
Dr. Rayson’s current address: Daniel Rayson,
M.D., London Regional Cancer Centre, 790 Commissioners Road East, London, Ontario, Canada
N6A 4L6.
Address for reprints: Dr. Patrick A. Burch, Division
of Medical Oncology, Mayo Clinic, 200 First Street
SW, Rochester, MN 55905.
Received September 26, 1997; revision received
January 14, 1998; accepted January 14, 1998.
© 1998 American Cancer Society
T
he relation between sarcoidosis and malignant disease remains
controversial. In an initial report by Brincker and Wilbek1 in 1974,
the incidence of malignant disease in patients with respiratory sarcoidosis reported to the Danish Institute of Clinical Epidemiology was
higher than expected because of an increased incidence of lymphoma
and lung carcinoma. No other solid tumors occurred at a higher than
expected rate in that study. Subsequent review of the reported cases
challenged these results, and the debate is ongoing.2– 4 The strongest
evidence for a relation that goes beyond chance association involves
lymphoma and sarcoidosis. Brincker5 proposed the existence of a
sarcoidosis-lymphoma syndrome after finding that malignant lymphoproliferative diseases developed 5.5 times more often than expected in middle-aged patients with chronic active sarcoidosis.
Solid tumors that have been purported to occur with a higher
than expected frequency in patients with sarcoidosis include lung and
breast carcinoma, and it has been suggested that immunologic abnormalities resulting from sarcoidosis might permit the development
338
CANCER July 15, 1998 / Volume 83 / Number 2
were seen between 1950 and 1996. A total of 14 patients are described, and to our knowledge represent
the largest case series reported in the literature.
METHODS
FIGURE 1. Biopsy specimen obtained at mediastinoscopy, demonstrating
noncaseating epithelioid granulomas.
of certain solid malignancies.3,6 However, solid data
from large surveillance studies are lacking to support
an etiologic relation.3,7
This review was prompted by a case of a 45-yearold man with a history of classic seminoma treated
with orchiectomy followed by whole abdominal irradiation in 1994. In 1996, a chest radiograph showed
extensive right hilar and paratracheal lymphadenopathy. He underwent mediastinoscopy, and biopsies revealed noncaseating epithelioid granulomas consistent with sarcoidosis (Fig. 1).
Several case reports and small case series have
described patients with sarcoidosis and testicular malignancy. Compared with other solid tumors, these
cases have been unique in that, in most instances, the
diagnosis of malignancy preceded that of sarcoidosis.4
The goals of this study were to determine the incidence of sarcoidosis in patients with malignant testicular tumors who were seen at our institution between
1950 and 1996 and to examine the relation between
these two diseases, particularly in regard to the therapy and follow-up of patients with testicular carcinoma.
This study describes all Mayo Clinic patients with
a malignant testicular tumor and sarcoidosis who
The medical record archive at the Mayo Clinic is a
comprehensive source of information regarding the
medical care of all patients seen at the clinic. A computerized search of the medical index at the Mayo
Clinic was used to identify all male patients with a
diagnosis of sarcoidosis and testicular tumor who
were seen between 1950 and 1996.
With the use of the same computer data base, the
total number of cases in which either sarcoidosis or
testicular carcinoma was reported as a diagnosis
among all men seen at the Mayo Clinic between 1976
and 1995 was ascertained. Estimated cumulative incidence rates were calculated based on the number of
cases of each disease evaluated during this period.
All charts were reviewed for clinical history, tumor
characteristics, radiologic and pathologic evaluation,
treatments, and follow-up and outcome information.
MEDLINE was searched for the key words testicular
tumor, malignant and sarcoidosis to identify all previous cases described in the world literature from 1966
to the present.
RESULTS
Of the 21 patients identified, 2 were females with
ovarian germ cell tumors, 1 patient had lymphoma, 1
had metastatic prostate carcinoma, and 1 had a benign testicular condition. Two patients had a primary
mediastinal germ cell tumor diagnosed concurrently
with pulmonary sarcoidosis, which likely represented
a local sarcoid-like tissue reaction. These seven patients were excluded from the analysis. The 14 remaining patients (Table 1) to our knowledge represent the
largest case series reported of testicular malignancy
and sarcoidosis.
The detailed characteristics of the patients are
presented in Table 2. The median age at diagnosis of
testicular carcinoma was 31.5 years (range, 18 –51
years). Eleven patients presented with Stage I disease
(confined to the testicle) and 3 presented with Stage II
disease (metastatic to retroperitoneal lymph nodes).
No patients had supradiaphragmatic disease (Stage
III) at presentation. Six patients had pure seminomatous tumors, three had nonseminomas, and five had
mixed histologic findings.
Of the 14 patients with primary testicular malignancy, 12 had their tumor diagnosed before sarcoidosis, and only 2 patients had sarcoidosis before carcinoma. For the 12 patients who had carcinoma before
sarcoidosis, the median interval between diagnoses
Sarcoidosis and Testicular Carcinoma/Rayson et al.
TABLE 1
Characteristics of 14 Patients with Testicular Malignancy and
Sarcoidosis Seen at the Mayo Clinic Between 1950 and 1996
Testicular carcinoma
Age at diagnosis (yrs)
Median: 31.5
Range: 18–51
Stage at diagnosis (no.)
I: 11
II: 3
III: 0
Histology (no.)
Pure seminoma: 6
Nonseminoma: 3
Mixed: 5
Metastatic sites (no.)
None: 9
Retroperitoneal lymph nodes: 4
Lung (?): 1
Sarcoidosis
Age at diagnosis (yrs)
Median: 36.5
Range: 20–53
Radiographic stage of disease (no.)
Stage I: 9
Testicular carcinoma (no.)
Stage II: 4
Stage III: 0
Extrapulmonary: 1
Extrapulmonary manifestations (no.)
Skin: 4
Ocular: 1
Hypercalcemia: 1
was 59.5 months (range, 24 –288 months). The median
duration of follow-up for this group was 124 months
(range, 24 – 420 months). All patients with primary testicular malignancy were without evidence of malignancy at last follow-up.
The median age at diagnosis of sarcoidosis was
36.5 years (range, 20 –53 years). Nine patients presented with radiographic Stage I disease (limited to
lymph node involvement), four patients presented
with radiographic Stage II disease (involving lung parenchyma and mediastinal lymph nodes), and one
patient had extrapulmonary disease. No patients presented with radiographic Stage III disease (parenchymal involvement alone). In one patient (Case 3), the
diagnosis was made at autopsy. All patients but one
had tissue confirmation of sarcoidosis. Five patients
had manifestations of extrapulmonary disease. Four
patients had skin involvement (Cases 7, 8, 12, and 14),
one had ocular involvement (Case 12), and one had
hypercalcemia (Case 9). Only one patient required
treatment of pulmonary sarcoidosis (Case 2). All other
treatments were administered for extrapulmonary
manifestations; these therapies included topical corti-
339
costeroids (Case 14), hydroxychloroquine (Case 14),
ocular corticosteroids (Case 12), and systemic corticosteroids with pamidronate for hypercalcemia (Case 9).
In all cases, disease either stabilized or underwent
spontaneous regression with no significant pulmonary
morbidity or death due to progressive sarcoidosis.
Forty-five previous cases have been reported in
the world literature. Twenty-one of the patients presented with a diagnosis of testicular tumor before
sarcoidosis,8 –19 8 had an antecedent diagnosis of
sarcoidosis,16,17,19,20 and 16 had concurrent diagnoses.16 –19,21–28
DISCUSSION
The diagnosis of sarcoidosis is made on the basis of a
compatible clinical history, exclusion of other causes
of granulomatous disease (such as tuberculosis, fungal
infections, or berylliosis), and tissue confirmation of
noncaseating granulomas.29 Diagnostic tests such as
determination of the serum angiotensin-converting
enzyme level, gallium scanning, and bronchoalveolar
lavage with analysis of the lymphocyte count and
T4/T8 subsets have low specificity and are not recommended for routine evaluation in suspected cases of
sarcoidosis, although they may be used as supportive
evidence in making the diagnosis. The Kveim test,
although highly specific and sensitive, requires precise
methodologic standardization and largely has been
replaced by direct tissue analysis as the standard for
confirmation of the diagnosis of sarcoidosis.30
Published incidence and prevalence rates of sarcoidosis vary widely among nations and among different
racial and geographic groups within the same country.31.32 In the U. S., data from large epidemiologic studies estimate the incidence of sarcoidosis to vary between
4 and 7.6 per 100,000 white males and to be approximately 10-fold higher among black males.33–35
However, the true incidence likely is considerably
higher because of the high frequency of asymptomatic
disease and because in the majority of cases the disease resolves spontaneously and thus never comes to
medical attention.35 Higher incidence rates have been
reported in persons with increased access to medical
care and among persons who undergo routine chest
radiographic screening for employment or immigration purposes.36
With use of the same computer data base, the
total number of cases in which either sarcoidosis or
testicular carcinoma was reported as a diagnosis
among all men seen at the Mayo Clinic between 1976
and 1995 was ascertained. There were 1839 diagnoses
of sarcoidosis and 1782 diagnoses of malignant testicular carcinoma during that period. Of the 14 patients
with primary testicular carcinoma and sarcoidosis re-
36
51
29
23
22
28
37
42
27
34
34
18
43
29
Case
1
2
3
4
5
6
7
8
9
10
11
12
13
14
T
S
S
S
E
S, E
T, E
?
S, E
S, E, T, C
S, A
S
S
S
Histology
None
RP lymph
nodes
None
None
?Pulmonary
nodule
RP lymph
nodes
None
None
RP lymph
nodes
RP lymph
nodes
None
None
None
None
Metastatic
sites
Orchiectomy, RPLND
Orchiectomy, RPXRT
Orchiectomy, RPLND,
chemotherapy
Orchiectomy, RPXRT
Orchiectomy, RPXRT
Orchiectomy, chemotherapy
Orchiectomy, RPLND,
Chemotherapy
Orchiectomy
Orchiectomy, RPLND
Orchiectomy, chemotherapy
Orchiectomy, RPLND
Orchiectomy, RPXRT
Orchiectomy mediastinal,
RPXRT
Orchiectomy, RPXRT
Treatment
Recurrence in
cervical lymph
node,
chemotherapy;
NED
NED
NED
NED
NED
NED
NED
NED
NED
Died of CAD, NED
testicular
carcinoma
Recurrence,
contralateral
testicle;
orchiectomy
and XRT
NED
Died of lymphoma;
NED testicular
carcinoma
NED
Outcome
Age at
diagnosis,
(yrs)
Sarcoidosis
Symptoms
38
45
30
108
36
37
20
35
32
49
45
29
24
36
24
91
60
144
36
80
28
Rash
None
None
None
Rash, eye pain
Hypercalcemia
None
Rash
Skin nodules
None
None
Yes
Yes
Yes
No
Yes
Yes
Yes
Skin
Skin
Yes
Yes
Yes
59
Dyspnea
Autopsy
49
Yes
Biopsy
Testicular malignancy before sarcoidosis
288 (autopsy) 53
None
24
Sarcoidosis before testicular malignancy
85
29
None
Interval
between
diagnoses,
(mos)
I
I
II
II
I
I
I
Extrapulmonary
I
I
I
I
II
II
Radiographic stagea
Topical steroids,
hydroxychloroquine
None
None
None
Ocular steroids
Steroids pamidronate
None
None
None
None
None
None
Steroids
None
Treatment
Progressive,
asymptomatic
disease, then
regression
Not available
Not available
Stable
Improved
Stable
Regression
Not available
Regression
Regression
Regression
Not available
Stable
Regression
Outcome
420
30
24
48
204
104
66
144
60
161
273
293
106
427
Total followup (mos)
a
S: seminoma; RPXRT: retroperitoneal external beam irradiation, NED: no evidence of disease; CAD: coronary artery disease; A: anaplastic, RPLND: retroperitoneal lymph node dissection; XRT: external beam irradiation; E: embryonal; T: teratoma; C: choriocarcinoma; RP: retroperitoneal
I indicates lymph node involvement only, whereas II indicates lymph node and lung parenchymal involvement.
Age at
diagnosis,
(yrs)
Testicular carcinoma
TABLE 2
Therapy and Outcome of 14 Patients with Testicular Malignancy and Sarcoidosis Seen at the Mayo Clinic Between 1950 and 1996
340
CANCER July 15, 1998 / Volume 83 / Number 2
Sarcoidosis and Testicular Carcinoma/Rayson et al.
ported in our series, in 12 the diagnosis of testicular
carcinoma was made during this interval and in 11 the
diagnosis of sarcoidosis was made during the same
period. The estimated cumulative incidence of sarcoidosis in the patients with testicular carcinoma seen
at the Mayo Clinic during this period was 617.3 per
100,000. Conversely, the estimated cumulative incidence of testicular carcinoma in the patients with
sarcoidosis was 652.5 per 100,000. Both these figures
are considerably higher than expected from population-based data, with the overall incidence of testicular carcinoma being 4.5 per 100,000 men in 199037 and
the incidence of sarcoidosis being 4 to 7.6 per 100,000
men.33–35 Our data are consistent with those reported
by Toner and Bosl,16 who estimated that the incidence
of sarcoidosis in patients with testicular germ cell
tumors seen at the Memorial Sloan-Kettering Cancer
Center between 1980 and 1989 was 510 per 100,000.
Testicular malignancy is the most curable of solid
tumors, with 3-year survival rates for all stages of
disease combined increasing from 89% to 96% between 1978 and 1987.37 Retroperitoneal lymph node
dissection after orchiectomy had been the mainstay of
treatment for disease localized to the testicle or with
evidence of spread to the retroperitoneum.38 However, with the advent of effective platinum-based chemotherapy, outcomes for patients with Stage I disease
who undergo orchiectomy without retroperitoneal
lymph node dissection (reserving systemic chemotherapy for recurrence) have been equal to those for
patients who undergo initial retroperitoneal lymph
node dissection.39 – 42 The efficacy of platinum-based
chemotherapy for even advanced, widely metastatic
disease makes the detection of recurrent disease of the
utmost importance and has led to intensive surveillance schedules for patients treated with curative intent. Accordingly, many institutions have adopted a
policy of close observation for reliable patients treated
with orchiectomy alone.41
This intensive surveillance makes diagnosis of an
asymptomatic case of sarcoidosis much more likely,
and thus surveillance bias is an important factor in the
interpretation of this case series on the relation between sarcoidosis and testicular malignancy. However, it is of interest that the median interval between
the diagnosis of sarcoidosis and testicular carcinoma
in this series was nearly 5 years (59.5 months), which
is beyond the period of the most intensive surveillance. Therefore, this finding somewhat militates
against surveillance bias being the sole factor behind
the high incidence observed in the current study.
The patients presented in this case series did not
differ significantly from those reported in the literature with regard to either testicular carcinoma or sar-
341
coidosis. The median age at diagnosis of testicular
carcinoma in our case series was 31.5 years. This conforms to the mean age at diagnosis of testicular carcinoma as ascertained by the Surveillance, Epidemiology, and End Results data base of 32 years, with the
diagnosis occurring between the ages of 20 and 44
years in 83.5% of all cases.37 The median age at diagnosis of sarcoidosis in our series was 36.5 years, which
is consistent with the data regarding age at presentation reported in the literature. The incidence of sarcoidosis is highest in the young adult population; up
to 70% of all patients are age , 40 years at presentation.32 In the Rochester, Minnesota, population-based
study, the peak incidence in males occurred between
ages 30 –39 years.35
All 14 patients in this series were without evidence
of recurrent testicular carcinoma at last follow-up, a
finding consistent with the 5-year relative survival
rates of 98 –99% for patients with local and regional
disease between the years 1986 and 1991.43 The four
patients who were treated with adjuvant systemic chemotherapy in our series did not experience any unusual toxicities. All patients had either stabilization or
spontaneous regression of sarcoidosis at last followup, and only one patient required treatment of pulmonary disease. This is in agreement with findings in
numerous reported series, in which only approximately 10% of patients with sarcoidosis required treatment for progressive respiratory disease, and has led
to close observation as the treatment of choice for
most stable cases because of the high rate of spontaneous regression.30
The high estimated cumulative incidence rates
reported in this study and that by Toner and Bosl16
must be interpreted cautiously in regard to a possible
etiologic association between the two conditions. Possibly, these figures represent the fortuitous association
of two uncommon conditions, both of which occur in
the same age group and one of which (sarcoidosis) is
discovered incidentally because of intensive surveillance after curative treatment of testicular carcinoma.
A spurious correlation may exist between these two
diseases because of the compounding of the independent probability of two diagnoses coexisting in a patient population drawn from a tertiary care center, a
phenomenon known as Berkson’s bias.44
The emphasis on detecting recurrent testicular
carcinoma is attributable to the efficacy of salvage
chemotherapy. Recognition of the general patterns of
tumor recurrence is important so as to avoid undertreatment of curable disease while avoiding overtreatment of a benign condition. Of interest, of the five
reported cases in which patients received chemotherapy for sarcoidosis, one with a fatal outcome,20 four
342
CANCER July 15, 1998 / Volume 83 / Number 2
have been reported since 1990. Undoubtedly, other
cases have gone unreported.
In general, isolated mediastinal lymph node recurrence of testicular carcinoma is uncommon. In a
series of 42 patients with recurrent nonseminoma,
Gels et al.41 found that only 2 patients (4.8%) had
recurrence solely in the mediastinum. Isolated supradiaphragmatic lymph node recurrence in pure seminoma is somewhat more common because of the use
of adjuvant abdominal irradiation in patients with
Stage I and II disease. Mediastinal involvement by
sarcoidosis is very common, with up to 50% of all
cases diagnosed as radiographic Stage I disease (involving mediastinal and hilar lymph nodes only).9
In cases of apparent mediastinal recurrence with
negative tumor markers, tissue confirmation is important to avoid potentially serious therapeutic error, but
it still may lead to diagnostic dilemmas. Sarcoid tissue
reactions can occur within a primary tumor, in the
lymph node basin draining a malignancy, or even in
distant lymph node sites. These reactions, which morphologically are identical to the noncaseating granulomas of systemic sarcoidosis, occur in up to 4.4% of
all carcinomas.45 We found two cases with concurrent
diagnoses of sarcoidosis and a mediastinal germ cell
tumor that are likely examples of this reaction. Further
study of the relation between these two entities should
eliminate this confounding situation by excluding
cases that are likely to represent local sarcoid tissue
reactions.
Subsequent study of the possible etiologic association between sarcoidosis and testicular malignancy
should be based on large, prospective surveillance
programs in which screening for sarcoidosis is performed in two cohorts of young men, one of which is
undergoing surveillance for recurrent testicular carcinoma and one of which undergoes the same intensity
of diagnostic testing (without tumor markers) at equal
intervals. Retrospective reviews of case series run the
risk of overestimating the strength of a possible relation because of inherent access and surveillance biases.
These two diseases possibly have an etiologic association, but the inherent biases of retrospective reviews limit the strength of this conclusion. The relation between testicular carcinoma and sarcoidosis
remains an interesting and clinically important field of
study, but any definite statement regarding a causal
relation awaits future investigation.
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