Keywords
Choriocarcinoma - GATA-3 - nongestational - primary - urinary bladder
Introduction
Choriocarcinoma is a malignant tumor of trophoblastic cells arising not only in the
uterus (gestational choriocarcinoma) but also rarely in extragenital locations such
as lungs, mediastinum, retroperitoneum, and in other ectopic sites (nongestational
choriocarcinoma). Choriocarcinoma arising in the urinary bladder is extremely rare
with only a handful of cases reported worldwide. Of these reported cases, very few
are “pure” choriocarcinoma with most of them being either poorly differentiated (high
grade) transitional cell carcinoma mixed with components of choriocarcinoma or mixed
germ cell tumor of the bladder.[1] Most of the nongestational choriocarcinomas described in the literature have been
found in either infants and young children or males. It is important to recognize
and give comprehensive diagnosis of primary nongestational “pure” choriocarcinoma
in comparison to conventional gestational choriocarcinoma, as they have poorer prognosis
and require stepped-up chemotherapy.[2] We, herein, report a case of primary “pure” choriocarcinoma of the urinary bladder
which was diagnosed in an unmarried, nulliparous, young girl who presented with the
history of recurrent hematuria.
Case Report
A 19-year-old female presented with the chief complaints of recurrent and painless
gross hematuria for the past 6 months with a single acute episode of gross hematuria
and pain in the hypogastrium before her admission to the gynecological outpatient
department. Her medical history revealed that she had been taking treatment from a
private center and was on and off on antibiotics throughout this period owing to her
clinical findings, although most of her culture reports were sterile. Her past as
well as her family history of any cancer was non-contributory. On general physical
examination, she was thin built and anemic. Per abdomen examination revealed mild
tenderness in the hypogastrium with no evidence of ascites or any organomegaly. She
had attained menarche at the age of 13 years and had regular cycles with an average
flow. Her gynecological examination was unremarkable. Her subsequent ultrasound pelvis
showed a nongravid everted uterus and unremarkable adnexa. On per rectal examination,
the rectal mucosa was free. All other systemic examinations were within the normal
limits. Her routine hematological investigations revealed microcytic hypochromic blood
picture. Urine and blood cultures were negative. Kidney and liver function tests were
normal. Serum antibodies to human immunodeficiency virus, hepatitis B surface antigen,
and syphilis were negative. X-ray chest was normal. To investigate the cause of hematuria,
cystoscopy was planned, which revealed hemorrhagic, polypoidal masses located at the
roof of the urinary bladder with extension toward the vaginal vault. During the cystoscopy,
a diagnostic biopsy was taken and was sent for histopathological examination. Microscopic
sections showed a deep infiltrative tumor showing sheets of trimorphic cells which
appeared highly bizarre exhibiting plexiform pattern with numerous giant cells. Sections,
in addition, showed marked central hemorrhage and striking atypia with numerous mitotic
figures [Figure 1]. On the basis of these findings, a differential diagnosis of extragonadal mixed
germ cell tumor with a predominant choriocarcinomatous component, undifferentiated
transitional cell carcinoma, and malignant mesenchymal tumor (sarcoma) of the urinary
bladder was made.
Figure 1: Microphotography exhibiting trophoblastic neoplasia with areas of necrosis
(H and E; ×200)
Immunohistochemistry (IHC) was advised. On IHC, the tumor was of epithelial cell origin
(pancytokeratin and high-molecular weight cytokeratin positivity and negativity for
desmin and vimentin) [Figure 2]a and b]. Epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), cytokeratin
20 (CK20), and uroplakin II were negative which excluded the diagnosis of de novo
high-grade (undifferentiated) urothelial carcinoma of the bladder [Figure 2]c. A further panel of markers proved it to be of germ cell origin (predominantly
choriocarcinomatous) as the tumor was positive for beta human chorionic gonadotropin
(β hCG), cytokeratin 7, p40, GATA-3, and p63 with high Ki-67 proliferation index of
80% [Figure 2]d and [Figure 3]. Other germ cell tumors were excluded from the study, on the basis of negative alpha-fetoprotein
(AFP), placental alkaline phosphatase (PLAP), CD-30, and CD-99 immunoexpression.
Figure 2: (a) Cytokeratin positivity (immunohistochemistry; ×400) (b) Vimentin negativity
(immunohistochemistry; ×400) (c) Uroplakin II negativity (immunohistochemistry; ×100)
(d) Ki-67 brisk positivity (immunohistochemistry; ×200)
Figure 3: (a) Beta human chorionic gonadotropin positivity (immunohistochemistry;
×400) (b) GATA-3 positivity (immunohistochemistry; ×400) (c) Focal p40 positivity
(immunohistochemistry; ×100) (d) Focal p63 positivity (immunohistochemistry; ×200)
To correlate the histopathological and immunohistochemical findings, serum β hCG levels
were advised which turned out to be very high (5000 IU/ml). Hence, a final diagnosis
of primary nongestational “pure” choriocarcinoma was rendered. The patient was referred
to higher apex center for further management. Unfortunately, she died 4 months after
the commencement of treatment with methotrexate and cisplatin, etoposide, bleomycin
(PEB) regimen due to pulmonary metastasis.
Discussion
Although the diagnosis of choriocarcinoma is easily established in females of reproductive
age group due to its strong association with pregnancy and higher β hCG levels, it
can cause diagnostic dilemma when it is associated with ectopic sites, children, unmarried
young girls, postmenopausal women, or in males where it is called as nongestational
choriocarcinoma.[3]
Embryologically, primitive germ cells migrate to gonadal ridge; hence, most of the
germ cells occur in gonads. However, germ cells can also aberrantly migrate to extragonadal
sites such as retroperitoneum, mediastinum, or in the present case, urinary bladder
as well. These germ cells have propensity to differentiate along different lines leading
to the presence of different elements in different stages of development which is
the hallmark of germ cell tumor.[4],[5] Several histogenetic mechanisms have been proposed to explain extragonadal origin
of choriocarcinoma with the most acceptable theory of migration failure by the remnant
population of germ cells in embryologically equivalent urogenital ridge.[6],[7]
The diagnosis of choriocarcinoma is usually based on the morphological assessment
of syncytiotrophoblasts and cytotrophoblasts such as elements and presence of high
β hCG levels. However, sometimes, this may not be sufficient for reaching the diagnosis
owing to the ambivalent clinical history and unusual tumor location.[8] In such situations, IHC plays a dynamic role in clinching the diagnosis.
IHC is to be interpreted accordingly so that there is no information overload leading
to generalized confusion. The algorithm in the present case was adopted where first
the mesenchymal origin was ruled out (negative immunoexpression for vimentin and desmin).
The epithelial cell origin was confirmed due to the presence of pancytokeratin and
high-molecular weight cytokeratin positivity. The next logical step was to ascertain
the tissue of origin where transitional cell (urothelial) was proved not to be the
histogenetic tumor epithelium as EMA, CEA, CK20, and uroplakin II were negative (excluding
the diagnosis of undifferentiated urothelial carcinoma). A further panel of germ cell
tumor markers was negative for AFP, PLAP, CD-30, and CD-99. Tumor cells, however,
were strongly positive for β hCG, thus confirming the initial suspicion of trophoblastic
origin of the tumor. An ancillary novel marker, GATA-3 was also employed which showed
positive immunoexpression. GATA-3 is a new molecule which is frequently expressed
in normal and trophoblastic lesions. In a recent study, it was shown to be strongly
expressed in trophoblastic neoplasms as well, and it was proposed that its expression,
if present, could be very helpful in differential diagnosis such as suspected metastatic
deposits in bladder or breast carcinoma involving the gestational organs.[9],[10] It is now thought to be very useful in diagnosing challenging neoplasms of trophoblastic
origin. Other positive ancillary markers p63 and p40 (which are employed to diagnose
squamous cell carcinoma) along with highly elevated serum β hCG levels corroborated
the final diagnosis of primary nongestational “pure” choriocarcinoma of the urinary
bladder. The final diagnosis included the term “pure” choriocarcinoma as no other
germ cell tumor component was identified on both light microscopy and on IHC as nongestational
choriocarcinoma may also have the germ cell components in 60% of the cases.[11]
In literature, most of the reported cases of primary choriocarcinoma of the urinary
bladder are highly aggressive and fatal presenting with early distant metastasis and
fast progression. Nongestational choriocarcinoma does not respond to conventional
methotrexate and PEB regimen which is usually given for cytoreduction but even with
this, response is seen in 73.3% of the patients and partial response in 11.1% of the
patients. That is why, in nongestational choriocarcinoma, quick diagnosis and aggressive
treatment are imperative.[12] In our case, although the tumor was confined to the bladder without any regional
or distant metastasis and the patient was started with aggressive chemotherapy at
a higher apex center, she later had pulmonary metastasis and the unfortunate demise
of the patient could not be prevented.
Conclusion
The case is worth reporting because of its rare clinical presentation and highlights
the role of IHC, especially the new/novel biomarkers such as GATA-3, p40, and p63
in reaching a conclusive diagnosis which might be diagnostically challenging for the
pathologists. This case report also proposes a probable algorithm of IHC markers in
all bizarre tumors of the urinary bladder revealed on light microscopy and one should
be aware of a possibility of primary choriocarcinoma arising in the urinary bladder.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms.
In the form the patient(s) has/have given his/her/their consent for his/her/their
images and other clinical information to be reported in the journal. The patients
understand that their names and initials will not be published and due efforts will
be made to conceal their identity, but anonymity cannot be guaranteed.
