Imaging, Diagnosis, Prognosis
Interphase Fluorescence In situ Hybridization Analysis
of Chromosome 12p Abnormalities Is Useful for
Distinguishing Epidermoid Cysts of the Testis
from Pure Mature Teratoma
Liang Cheng,1,2 Shaobo Zhang,1 Gregory T. MacLennan,3 Christopher K. Poulos,1
Ming-Tse Sung,1,4 Stephen D. Beck,2 and Richard S. Foster2
Abstract
Purpose: The distinction of epidermoid cyst of the testis from teratoma is of critical importance
because the former is benign and the latter is a malignant tumor that may have associated metastasis of either teratomatous or non ^ teratomatous germ cell tumor types. Chromosome 12p
abnormalities are seen in the vast majority of testicular germ cell tumors of adults and are present
in all histologic subtypes. In this study, we investigated the clinical utility of interphase fluorescence in situ hybridization (FISH) analysis of chromosome 12p abnormalities for distinguishing
epidermoid cysts of the testis from pure mature teratoma.
Experimental Design: Sixteen testicular epidermoid cysts and 17 testicular teratomas were
investigated for isochromosome 12p [i(12p)] and 12p overrepresentation using interphase FISH
analysis.
Results: Neither i(12p) nor 12p overrepresentation were observed in 16 epidermoid cyst cases,
whereas i(12p) was detected in 76% of teratomas and 12p overrepresentation was identified in
29% of teratomas. Overall, 88% of testicular teratomas had chromosome 12p abnormalities.
Conclusions: FISH identification of i(12p) and/or 12p overrepresentation in routinely processed
surgical specimens is a useful ancillary diagnostic tool in distinguishing testicular epidermoid cysts
from teratoma.
Epidermoid cyst of the testis is an uncommon benign lesion
accounting for <1% of all testicular tumors (1). Several authors
have hypothesized that it originates from squamous metaplasia
of the mesothelium, rete testis epithelium, or seminiferous
tubular cells; others believe that it represents a monodermal
teratoma (1, 2). The main differential diagnostic consideration
of epidermoid cyst is teratoma of the testis. This distinction is
critically important for prognosis and patient management.
Unlike its ovarian counterpart, teratoma of the testis is a
malignant neoplasm with a high incidence of metastasis. After
complete removal of the tumor by orchiectomy, additional
treatments, including retroperitoneal lymph node dissection
and chemotherapy, may be considered for patients with
Authors’ Affiliations: Departments of 1Pathology and Laboratory Medicine, and
2
Urology, Indiana University School of Medicine, Indianapolis, Indiana;
3
Department of Pathology, Case Western Reserve University, Cleveland, Ohio;
and 4 Department of Pathology, Chang Gung Memorial Hospital-Kaohsiung
Medical Center, Chang Gung University, College of Medicine,Taiwan
Received 4/21/06; revised 7/6/06; accepted 7/14/06.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
Requests for reprints: Liang Cheng, Department of Pathology and Laboratory
Medicine, Indiana University School of Medicine, 350 West 11th Street, Clarian
Pathology Laboratory, Room 4010, Indianapolis, IN 46202. Phone: 317-4916442; Fax: 317-491-6419; E-mail: lcheng@ iupui.edu.
F 2006 American Association for Cancer Research.
doi:10.1158/1078-0432.CCR-06-0976
Clin Cancer Res 2006;12(19) October 1, 2006
testicular teratoma. In contrast, complete removal of the lesion
by surgery is curative for epidermoid cyst of the testis (3).
Distinguishing testicular epidermoid cyst from teratoma can
be a challenging exercise. A number of well-established
histologic criteria have been proposed for use in making this
distinction (4). Other than these proposed histologic criteria,
no useful diagnostic techniques have been developed to aid in
this diagnostic dilemma. It would be helpful to identify a
sensitive and specific molecular test, applicable to paraffinembedded tissue, which would assist in this process.
Chromosome 12p abnormalities (either as isochromosome
12p [i(12p)]or 12p overrepresentation) are seen in the vast
majority of testicular germ cell tumors and have been observed
in all histologic subtypes (5, 6). In this study, we investigated
whether interphase fluorescence in situ hybridization (FISH)
analysis of chromosome 12p abnormalities is useful in
distinguishing epidermoid cysts of the testis from testicular
teratoma using paraffin-embedded tissue.
Materials and Methods
Patients and specimens. Sixteen cases of prepubertal and postpubertal testicular epidermoid cyst and 17 cases of postpubertal pure
testicular teratoma were retrieved from the surgical pathology files of
the Indiana University School of Medicine (Indianapolis, IN) and Case
Western Reserve University (Cleveland, OH) from 1992 to 2000. One
epidermoid cyst in a seven-year-old boy was treated by partial
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FISH in the Diagnosis of TesticularTumors
orchiectomy only; the remainder of the tumors were treated by radical
orchiectomy. This research was approved by the Indiana University
Institutional Review Board.
FISH analysis. FISH test was done as previously described (7 – 11).
Four-micrometer sections were prepared from buffered formalin-fixed,
paraffin-embedded tissue blocks. The slides were deparaffinized with
two 15-minute washes of xylene, and were subsequently washed twice
with absolute ethanol for 10 minutes each. The slides then were airdried in a fume hood. Next, the slides were treated in 0.1 mmol/L of
citric acid (pH 6.0; Zymed, Carlsbad, CA) at 95jC for 10 minutes,
rinsed in distilled water for 3 minutes, and washed with 2 SSC for
5 minutes. Digestion of the tissue was done by applying 0.4 mL of
pepsin (5 mg/mL in 0.9% NaCl, pH 1.5; Sigma, St. Louis, MO) at 37jC
for 40 minutes. The slides were rinsed with distilled water for
3 minutes, washed again with 2 SSC for 5 minutes, and air-dried.
Dual-color FISH was done by using a mixture of Spectrum Orange –
labeled centromeric a satellite DNA probe (CEP12) and Spectrum
Green – labeled subtelomeric (Tel12) DNA probes for chromosome 12p.
Both of the probes were from Vysis (Downers Grove, IL) and were
diluted with tDenHyb2 (Insitus, Albuquerque, NM) in a ratio of 1:50
and 1:20, respectively. Five microliters of diluted probes were added
to the slide in the reduced light condition, slides were covered with a
22 22 mm coverslip, and were sealed with rubber cement. Denaturation was achieved by incubating the slides at 75jC for 10 minutes
in a humidified box, then the slides were hybridized at 37jC overnight.
The coverslips were removed and the slides were washed extensively
twice with 45jC prewarmed 0.1 SSC/1.5 mol/L urea, for 20 minutes
for each, followed by a wash with 2 SSC for 20 minutes and 2 SSC/
0.1% NP40 for 10 minutes at 45jC. The slides were further washed with
room temperature 2 SSC for 5 minutes. The slides were air-dried and
counterstained with 10 AL of 4¶,6-diamidino-2-phenylindole (DAPIAntifade Insitus). The slides were covered and sealed with nail polish.
The slides were examined using a Zeiss Axioplan 2 microscope
(Göettingen, Germany) with the following filters: SP-100 DAPI, FITC
MF-101 for Spectrum Green (12p) and Gold 31003 for Spectrum
Orange (CEP12) from Chroma (Brattleboro, VT).
The images were acquired with a CCD camera and analyzed with
MetaSystem Isis software (Belmont, MA). Five sequential focus stacks
with 0.4-Am intervals were acquired and then integrated into a single
image in order to reduce thickness-related artifacts.
From each tumor section, 100 nuclei were scored for signals from
CEP12 (red) and 12p (green) under the fluorescence microscope with
1,000 magnification, and the ratio between green and red signals was
subsequently calculated. We analyzed the spatial distribution of the
green and red signals to detect the specific patterns of signal aggregation
consistent with i(12p), as previously reported (5, 12 – 16). The
quantitative criteria to determine 12p overrepresentation have been
described previously (15 – 17).
A classical seminoma specimen was used as a positive control for
FISH analyses. Lymphocyte and stromal nuclei from the same tumor
were used as normal controls for each tumor. In addition, we analyzed
six cases of skin punch biopsies from patients without a history of germ
cell tumors.
Results
Sixteen cases of prepubertal and postpubertal testicular
epidermoid cyst and 17 cases of postpubertal testicular
teratoma were investigated for i(12p) and 12p overrepresentation. Patients with epidermoid cyst ranged in age from 7 to 44
years old (mean, 22) and those with mature teratoma ranged in
age from 23 to 46 years old (mean, 33) at the time of the initial
diagnosis.
All of the slides showed well-defined hybridization signals.
Neither i(12p) nor 12p overrepresentation was observed in 16
epidermoid cyst cases (Fig. 1). Overall, 88% of testicular
www.aacrjournals.org
teratomas had chromosome 12p abnormalities (either i(12)p
and/or 12p overrepresentation; Table 1). i(12p) was detected in
13 of 17 (76%) teratomas in a percentage of nuclei ranging
from 2% to 5%, and 12p overrepresentation was observed in
5 of 17 mature teratomas (29%; Fig. 1). Among the 13 cases of
i(12p)-positive mature teratomas, 3 cases (24%) also had 12p
overrepresentation. Three of the five cases (60%) with 12p
overrepresentation also had i(12p). Only 2 of 17 cases (12%)
showed neither 12p overrepresentation nor the presence of
i(12p) (Table 1). Neither i(12p) nor 12p overrepresentation
was observed in lymphocytes or stromal cells from the study
patients or keratinocytes from skin punch biopsy specimens.
Discussion
Epidermoid cysts were first described in 1942 by Dockerty
and Priestly (18). They are uncommon, and are composed of
cysts lined by squamous epithelium. Epidermoid cysts account
for f1% of adult testicular tumors (1) and 3% of pediatric
testicular tumors (3), although in some studies, they have
comprised up to 4% of testicular tumors (19). Many authors
consider them to be monodermal teratomas (1, 4). Evidence
supporting the teratomatous nature of testicular epidermoid
cysts includes the fact that the age range of their occurrence
overlaps with that of recognized germ cell tumors, and that
morphologically typical epidermoid cysts are sometimes found
to be components of classic teratomas. However, unlike the
majority of teratomas in males, epidermoid cysts are not
associated with mitotic activity, cytologic atypia, intratubular
germ cell neoplasia of the unclassified type, or testicular
atrophy (4), and uniformly exhibit benign clinical behavior
(1, 2, 20 – 22). Price (1) reported a large series of 69 cases of
testicular epidermoid cysts, all of which were characterized by
an unremarkable clinical course, with a period of follow-up
ranging from 1 to 24 months (22). Because epidermoid cyst of
the testis is a benign tumor that is amenable to conservative
therapy, as opposed to testicular teratoma, which requires
radical orchiectomy, evaluation for metastasis, and sometimes
adjuvant chemotherapy, it is of paramount importance to
distinguish one from the other.
The hallmark genetic markers of testicular germ cell tumors
are chromosome 12p anomalies, including i(12p) and 12p
overrepresentation (6). Abnormalities of 12p have been shown
to occur early in the evolution of germ cell tumor (23, 24).
Recent studies have shown that FISH analysis is the most
sensitive method to detect i(12p) (24). In this study, we
analyzed a series of 16 epidermoid cysts and 17 testicular
teratomas by dual-color FISH technologies and found 12p
abnormalities in 88% of teratoma cases but none in the 16
epidermoid cyst cases. Our study showed that testicular
epidermoid cysts are genetically different from testicular
teratomas and interphase FISH analysis of chromosome 12p
abnormalities may be useful to distinguish testicular epidermoid cysts from testicular teratomas. When a testicular tumor is
managed by radical orchiectomy, the distinction between
teratoma and epidermoid cyst is not usually difficult and
probably does not require FISH analysis; however, conservative
surgery may be indicated in patients with cystic masses, solitary
testis, or infertility, in an effort to preserve testicular parenchyma. In these cases, the pathologist may have a more difficult
time distinguishing between the two entities, and the use of
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Imaging, Diagnosis, Prognosis
Fig. 1. A, testicular teratomas are complex tumors, often demonstrating
components derived from all three embryonic germ layers (37).
B, epidermoid cyst shows benign-appearing squamous epithelium lining
the cyst, the lumen of which contains layers of keratin. C, the adjacent
seminiferous tubules are normal. FISH analysis displays i(12p) in teratoma.
Two orange signals for chromosome 12 centromeric probe and three green
signals for 12p are present in the cell in the center of the image. Two of
the 12p signals are in close proximity to one centromeric signal, with an
aggregation pattern (arrow) consistent with i(12p). D, FISH analysis also
shows chromosome 12p overrepresentation in teratoma, characterized
by two red signals for the chromosome 12 centromere and numerous green
signals for the 12p subtelomeric probe. E, FISH pattern typical of
epidermoid cyst (disomic chromosome 12 signals).
FISH analysis could aid in the distinction of these entities in
locally excised masses. However, teratomas of the testis in
prepubertal boys are not malignant, and thus, the distinction
between teratoma and epidermoid cyst is not critical in this age
group.
The genetic abnormalities associated with epidermoid cysts
have not been extensively investigated. A study by Younger et
al. showed that epidermoid cysts have different loss of
heterozygosity patterns from malignant germ cell tumors,
emphasizing a lack of similarity with these tumors (25). In
contrast, the genetic abnormalities associated with testicular
germ cell tumors have been thoroughly evaluated, including
many studies that have evaluated 12p abnormalities in
testicular germ cell tumors. These studies include classic
cytogenetic analyses, FISH on metaphase cells of fresh tissue,
Clin Cancer Res 2006;12(19) October 1, 2006
FISH on interphase cells from paraffin-embedded tissue, and
comparative genomic hybridization. Standard cytogenetics
detects i(12p) in 50% to 70% of testicular germ cell tumors
(26). The i(12p)-negative cases, however, showed other 12p
abnormalities (27). Using FISH, Smolarek et al. (28), evaluated
11 primary germ cell tumors and 16 metastatic germ cell
tumors involving lymph nodes, and found overrepresentation
of 12p in all 27 tumors. Other studies, including comparative
genomic hybridization, have also characterized the overrepresentation of 12p in testicular germ cell tumors. Mostert et al.
examined 15 primary testicular germ cell tumors and two
metastatic germ cell tumors and observed that gain of 12p in
the majority of the tumors involved the complete short arm of
chromosome 12 (29). Abnormalities of 12p in testicular
teratomas have been shown to occur early in the evolution of
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FISH in the Diagnosis of TesticularTumors
Table 1. FISH analysis of i(12p) and 12p amplification in epidermoid cyst and mature teratoma of the testis
Epidermoid cyst
Case no.
i(12p)
Mature teratoma
12p Overrepresentation
Case no.
i(12p)
12p Overrepresentation
+
+
+
0%
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Average
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Average
0%
germ cell tumors, with some evidence that 12p amplification is
required for the development of an invasive tumor (6, 24).
Before the dual-color FISH technique became readily
available, i(12p) was mainly analyzed by comparative genomic
hybridization and/or metaphase chromosome banding methods (30, 31). Using the FISH method, the reported percentage
of i(12p)-positive cells ranged from 2% to 8% for a given case
(24, 32, 33), with the exception of an early study in which
i(12p) was recognized by chromosome centromeric signal size;
in that study, 50% to 90% of the cells were reportedly positive
for i(12p) (34). In the current study, we used stringent criteria
for the identification of i(12p) by interphase dual-color FISH.
Only cells that have both the specific signal number and signal
spatial relationship are recorded as i(12p)-positive (15, 16).
The strict criteria adapted in the current study assured high
specificity for the identification of i(12p), but this may also
contribute to the limited number of cells being recognized as
i(12p)-positive tumor cells. Nonetheless, the percentage of
i(12p)-positive cells (2-5%) reported here in mature teratoma is
comparable to the percentages reported in the literature cases
+
+
+
+
+
+
+
+
+
+
+
+
76%
+
+
+
29%
(32, 35, 36). Because the percentage of cells with recognizable
i(12p) signals in germ cell tumors is typically quite low (2-5%),
tissues with cell types comparable with those in the studied
lesion (e.g., normal squamous epithelium) would serve as
optimal controls. FISH assays are best validated when negative
controls contain nuclei of similar size to those in the studied
sample. This is important because nuclear truncation and
overlap-related artifacts are important factors in establishing a
negative range for routine assays.
In conclusion, epidermoid cysts are rare, benign testicular
neoplasms that are genetically distinct from testicular teratoma
because they lack abnormalities in chromosome 12p, including
i(12p) and chromosome 12p overrepresentation. Molecular
testing for chromosome 12p abnormalities is a rational
approach to the distinction of a testicular epidermoid cyst
from a testicular teratoma. FISH identification of i(12p) and/or
12p overrepresentation in routinely processed surgical specimens is a useful ancillary diagnostic tool for making this
distinction, providing strong support for a diagnosis of
teratoma.
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Interphase Fluorescence In situ Hybridization Analysis of
Chromosome 12p Abnormalities Is Useful for Distinguishing
Epidermoid Cysts of the Testis from Pure Mature Teratoma
Liang Cheng, Shaobo Zhang, Gregory T. MacLennan, et al.
Clin Cancer Res 2006;12:5668-5672.
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