Case 4 -
Seminoma with Microcystic Pattern
Thomas M. Ulbright
Click on each slide thumbnail image for an enlarged view
A 27-year-old man presented with a 3-week history of an enlarging right testicular mass.
An orchiectomy was performed. On gross examination, there was a 5.5 cm, fleshy, well-circumscribed tumor
that bulged above the adjacent parenchyma. A separate 0.6 cm nodule was also noted.
Case 4 - Figure 1 - The tumor forms anastomosing islands with diffuse microcystic change.
Case 4 - Figure 2 - Intermediate magnification shows smaller islands of tumor with microcystic change in a prominently hyalinized stroma.
Case 4 - Figure 3 - The microcysts are mostly round and regular and appear empty.
Case 4 - Figure 4 - A high magnification shows the cytological features of the tumor cells.
Diagnosis Seminoma with microcystic pattern
Seminoma is the most common form of testicular tumor, representing 50% of the germ cell
tumors,  which in turn comprise 95% of all testicular neoplasms. Its accurate diagnosis is
especially important, not only because of its relative frequency but also because its treatment is often
different compared to other testicular tumors. Patients with early stage seminoma usually receive either
adjuvant (clinical stage I) or therapeutic (clinical stages IIA and IIB) radiation, whereas those with
non-seminomatous germ cell tumors are typically managed by combinations of surveillance, chemotherapy and
surgery, depending on their stage. Although most seminomas are easily recognized based on the
characteristic sheet-like arrangement of cells with pale to clear cytoplasm that is further subdivided by
lymphocyte-containing fibrovascular septa, uncommon and deceptive patterns can occur that make the
diagnosis of seminoma difficult.
In 1964 Thackray, in a monograph derived from the experience of the British Testicular Tumour Panel,
mentioned that cystic change could occasionally be identified in seminomas and attributed its occurrence
to edema.  In 1980, Damjanov et al reported a case of
"cribriform and sclerosing seminoma devoid of lymphoid infiltrates".  This tumor had
multiple nests of seminoma cells in a prominently hyalinized stroma; within the cell nests there were
multiple small spaces, yielding a microcystic or cribriform pattern. Similar cases have also been
illustrated in chapters for textbooks  and in the 3rd series AFIP tumor fascicle,
 but there has been no formal study of such unusual seminomas in a series of cases. We
recently studied 28 cases of seminoma with microcystic change that varied from focal to diffuse.
 There was nothing unusual about the clinical or gross features of these cases, with the
patients being in the usual age range for seminoma (21 – 55 years), most presenting with a testicular
mass, and the tumors having the typical solid, cream-colored to tan appearance. On microscopic
examination, however, all of the tumors had small to more dilated spaces that varied from irregular in
size and shape to relatively uniform, round and regular. The development of such spaces caused concern
for microcystic yolk sac tumor, a differential consideration that was made more difficult by the paucity
or absence of lymphocytes in many of these tumors, similar to the case reported by Damjanov and coworkers
 . Granular, eosinophilic edema fluid was present in the spaces of some of the cases, but
many cases lacked edema fluid and many spaces in those cases with edema appeared empty, so edema does not
appear to provide a uniform explanation for this phenomenon. In addition to microcysts, twelve tumors
also had distinct tubular patterns with either hollow or solid profiles, a finding previously reported in
seminoma that potentially mimics Sertoli cell tumor.
The most important finding in cases of microcystic seminoma that serves to distinguish them from other
diagnostic considerations, especially yolk sac tumor, is the retained cytological features of seminoma.
The cells lining the spaces have the usual seminoma features - polygonal cells with nuclei having
prominent nucleoli and "squared off" nuclear membranes. On the other hand, the microcysts of yolk sac
tumor are lined by cells that often have flattened contours, and the adjacent cells are more pleomorphic
rather than showing the more monomorphic appearance of seminoma cells. The microcysts of yolk sac tumor
also tend to have more complex, anastomosing patterns rather than the predominance of separate,
individual spaces in the seminomas. For those cases with a prominent tubular pattern, where the
differential diagnosis includes Sertoli cell tumor, the lower grade nuclei with less prominent nucleoli
and lower mitotic rate of the latter contrasts with the features of seminoma,  as does the
absence of intratubular germ cell neoplasia of the unclassified type (IGCNU) in Sertoli cell tumor,
whereas IGCNU occurs with seminoma in excess of 90% of the cases.  Immunostains are also
helpful in resolving these differentials; seminomas are negative for alpha-fetoprotein and usually
negative or only focally reactive for AE1/AE3 cytokeratins.  On the other hand they are
strongly and diffusely positive for OCT3/4 (POU5F1) protein, which appears currently to be the most
sensitive seminoma marker, with very high specificity for seminoma and embryonal carcinoma and with no
false negative reports to date.
In contrast, yolk sac tumors show opposite reaction
patterns with these three markers. The very high specificity of OCT3/4 protein staining for seminoma and
embryonal carcinoma, with only focal staining in occasional ovarian clear cell carcinomas and rare clear
cell renal cell carcinomas and non-small cell carcinomas of the lung,
should be contrasted
with the low specificity of two other markers that are commonly employed as a positive stain for
seminoma, placental alkaline phosphatase and c-Kit (CD117), both of which stain numerous other tumors of
both germ cell and non-germ cell type. The distinction from Sertoli cell tumor is facilitated by
immunostains against inhibin, OCT3/4 protein and placental alkaline phosphatase, with inhibin often being
positive in Sertoli cell tumor but negative for the latter two markers, and seminoma having opposite
Seminomas may have other deceptive patterns apart from microcystic and tubular arrangements. Focal
intertubular growth is common in seminomas, occurring in over half of unselected cases.  It
is, however, very uncommon for intertubular growth to be the only pattern in a seminoma; such cases of
purely intertubular seminoma typically present with metastases or infertility rather than a testicular
mass.  Even on gross examination of the orchiectomy specimens in such cases there is usually
no distinct mass but areas of firmness or discoloration with respect to the adjacent parenchyma. On
microscopic examination, intertubular growth is often inconspicuous, consisting of small clusters and
individual tumor cells growing between intact seminiferous tubules. In many examples, there is an
associated lymphocytic infiltrate, which can potentially obscure the tumor cells but also serve to call
attention to them. Admixture of seminoma cells with clusters of hyperplastic Leydig cells is also common
in intertubular seminoma. In some cases the intertubular seminoma cells have a plasmacytoid appearance,
with somewhat eccentrically placed nuclei and more densely staining cytoplasm than the usual pale to
clear cytoplasm of most seminomas. In conjunction with the intertubular growth, these features may
provoke concern for lymphoma or plasmacytoma. The detection of intertubular seminoma cells, however, can
be considerably facilitated by utilizing immunostains such as placental alkaline phosphatase, c-Kit and
OCT3/4, which also serve to distinguish them from potential hematopoietic mimickers. The possible
diagnostic problem, however, must be recognized by routine H&E morphology, with careful attention to
areas of lymphocytic infiltrates and Leydig cell clusters.
Atypical features can occur in seminoma where the tumor cells have more densely staining cytoplasm,
less well-defined cytoplasmic membranes and greater nuclear pleomorphism.  These changes
cause concern for solid pattern embryonal carcinoma, a realistic consideration given that seminoma is now
recognized as a tumor capable of transforming into many of the non-seminomatous germ cell tumors,
including embryonal carcinoma.  If such atypical foci show any evidence of epithelial
differentiation, including glands or papillary structures, a non-seminomatous component should be
diagnosed. In the absence of such distinct epithelial differentiation, immunostains can be helpful in
deciding if such cases represent transformation of seminoma to embryonal carcinoma; if there is selective
highlighting of such atypical foci by AE1/AE3 cytokeratins and CD30, there is justification for an
embryonal carcinoma component since seminoma is usually negative or only focally reactive for these
antigens in contrast to embryonal carcinoma, which usually expresses them strongly.
On rare occasions, a diffuse granulomatous reaction in a seminoma makes the tumor cells inconspicuous,
thereby mimicking idiopathic granulomatous orchitis. Patients with idiopathic granulomatous orchitis,
however, often have a prodromal syndrome suspicious for an infectious process, and many have a history of
a pre-existing urinary tract infection.
They often have pain and swelling. On the
other hand, patients who present with seminoma typically have no prodromal symptoms and
characteristically present with a painless mass, although certainly some may have a degree of testicular
tenderness. On gross examination, the typical example of idiopathic granulomatous orchitis represents a
diffuse involvement of the testicular parenchyma, yielding a tan to yellow, uniform pattern, although
exceptionally a distinct nodule may be formed. Although some seminomas, notably those with prominent
intertubular patterns, may have a similar appearance, it is much more common for seminomas to show a
distinct intratesticular mass. On microscopic examination, idiopathic granulomatous orchitis will often
display a prominently tubulocentric granulomatous reaction, with a diffuse lymphoplasmacytic infiltrate
in the interstitium, whereas the classic granulomatous reaction in seminomas has a greater interstitial
component. In my experience, however, there is too much overlap in patterns for this to be of practical
diagnostic utility in an individual case, with some seminomas displaying conspicuous intratubular
granulomatous reactions. Extensive sectioning of any testicular specimen with a prominent granulomatous
reaction is therefore indicated to evaluate for the presence of residual seminoma cells; use of
appropriate immunostains is also very helpful in this circumstance to highlight seminoma cells that are
made inconspicuous by the inflammation and granulomatous reaction. Identification of IGCNU in such cases
may be crucial in supporting the diagnosis of an underlying seminoma.
There are two additional lesions that may cause confusion of seminoma with a non-seminomatous germ
cell tumor. These, however, are not patterns of the tumor but potentially deceptive changes induced by
involvement of secondary structures by seminoma or by its precursor. When any neoplasm invades into the
rete testis it may induce a secondary hyperplasia of the rete epithelium with the formation of small
cystic spaces and hyaline globules within the epithelium.  In florid examples this reaction
can be mistaken for yolk sac tumor because of the combination of a microcystic pattern and hyaline
bodies. The keys to its recognition are the low power arborizing architecture of the rete epithelium and
the bland cytological features of the hyperplastic rete epithelium. Additionally, sometimes there is
extensive involvement of the rete testis by IGCNU associated with a seminoma.  The IGCNU
cells undermine the rete epithelium in a pagetoid fashion and continue to proliferate, compressing the
rete epithelium into rather inconspicuous flattened cells and greatly expanding the volume of the rete
testis. The luminal spaces of the rete testis may resemble the luminal spaces of individual glands,
causing concern for embryonal carcinoma or yolk sac tumor. The key in this situation is to identify the
typical cytological features of the seminoma-like cells of IGCNU, appreciate the compressed rete
epithelial cells, and note the overall architectural pattern of the rete testis.
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