Keywords
epithelioid trophoblastic tumor - gestational trophoblastic neoplasia - placental
site trophoblastic tumor
Introduction
Epithelioid trophoblastic tumor (ETT) is the rarest of gestational trophoblastic neoplasia
(GTN) with an incidence of 2.2% of all GTNs.[1] It develops from neoplastic transformation of intermediate trophoblastic cells (ITC).
Intermediate trophoblastic tumors exhibit exaggerated placental site, placental site
nodule (PSN), placental site trophoblastic tumor (PSTT), and ETT. Implantation type
gives rise to PSTT and chorionic type results in ETT. That is the reason both behave
similarly and are distinguished mainly by immunohistochemistry (IHC).
Case Report
A woman aged 45 years who had attained menopause 3 years back had presented to an
outside hospital with retention of urine. She is para 2 living 2 with her last child
birth 13 years back which was a full-term delivery. Prior cycles were regular, and
now she did not have postmenopausal bleeding. On evaluation by ultrasound (US) and
magnetic resonance imaging ([Fig. 1]), it showed a solid cystic pelvic mass with calcification of 8 × 10 × 7 cm predominantly
on the left side involving the uterus with nonvisualized left ovary with an impression
of neoplastic etiology of either ovarian or uterine origin. No ascites or pelvic lymphadenopathy
was noted. The tumor marker CA-125 level was 14.6 U/mL. She underwent exploratory
laparotomy in that hospital where a uterine tumor was noted infiltrating the bladder
anteriorly. Total abdominal hysterectomy with bilateral salpingo-oophorectomy with
excision of bladder flap was done. The gross specimen of the uterus showed a tumor
size of 8 × 7.5 × 5 cm occupying the lower uterine segment breaching the serosa in
the left lateral aspect of the uterus infiltrating the bladder. Microscopy showed
epithelioid tumor cell nests with necrosis and calcification with atypical features
and a 4 mitosis/10 hpf (high power field) was noted ([Fig. 2]). Tumor cells were seen involving the adjacent fallopian tube and ovary. The International
Federation of Gynecology and Obstetrics (FIGO) stage II was reported as the tumor
extends to other genital organs. IHC was asked for confirmation. The patient came
to us with an IHC report for further management. IHC markers of cytokeratin (CK) 8/18,
P63, and inhibin were positive. SALL4, desmin, and GATA3 were negative. Ki-67 was 20% ([Fig. 3]). After seeing the histopathological report, β human chorionic gonadotropin (β-hCG)
was done and was 4.47 mIU/mL.
Fig. 1 Magnetic resonance imaging showing pelvic mass infiltrating the bladder.
Fig. 2 Microscopy (hematoxylin and eosin stain) showing nests of epithelioid cells with
atypical features, with hyalinization and necrosis.
Fig. 3 Immunohistochemistry of tumor cells showing positive expression for cytokeratin (CK8/18),
P63, inhibin and negative for β-human chorionic gonadotropin (β-hCG).
A metastatic workup of chest X-ray, β-hCG, and computed tomography (CT) of the lung,
abdomen, and pelvis was done and found to be normal. Her FIGO score was 9 (high risk:
>40 years old [45 years = 1], index pregnancy [term delivery = 2], time since delivery
[13 years = 4], β-hCG (4.47 mIU/mL = 0), size of the tumor (>5 cm = 2), metastasis
(none = 0), number of metastasis (none = 0), and previous failed chemotherapy drugs
(no = 0). After discussing with the medical oncologist, we came to a decision even
though there was no metastasis, we planned to give adjuvant chemotherapy as her antecedent
pregnancy was >4 years, and the excised bladder flap margin was not free of tumor
cells. Three cycles of etoposide, methotrexate, actinomycin-D, cyclophosphamide, and
oncovin (EMA/CO) were planned. The patient received three cycles of the multiagent
chemotherapy and has been called for follow-up after 4 weeks. We planned to follow
her up regularly with an examination, β-hCG levels, US/contrast-enhanced CT of the
abdomen and pelvis for a minimum period of 5 years. The tumor board had decided to
only give adjuvant chemotherapy and to follow-up regularly to look for recurrence.
Since ETT is radioresistant tumor, radiotherapy was not considered.
Discussion
GTN is a malignant transformation of a gestational event which consists of invasive
mole, choriocarcinoma, PSTT, and ETT. Initially, ETT was termed as atypical choriocarcinoma,
later Shih and Kurman in 1998 called it as ETT. It is commonly seen in reproductive
age group of 15 to 48 years (mean 36 years).[2] Very few cases are reported in postmenopausal age group. Though our patient is 45
years old, she had attained menopause 3 years ago. Most of the patients (67%) present
with irregular vaginal bleeding. Other symptoms include abdominal pain, abdominal
distension, amenorrhea, or symptoms due to metastasis. Many at times it is incidentally
found in a hysterectomy specimen[3] or dilatation and curettage sample. Here, patient had presented with urinary retention
probably because the tumor was infiltrating the bladder. Uterus is the primary site
(40%) especially the lower uterine segment just like in this case. The next site which
is commonly involved is cervix (31%) and can be confused to squamous cell carcinoma
(SCC) of the cervix. The commonest extrauterine site is lung (19%) and other sites
where tumor can arise include broad ligament, fallopian tube, ovary, pelvis, and vagina.
There are few cases of only isolated lung lesions without any uterine involvement.
The tumor size usually ranges from 0.5 to 4 cm. The tumor is usually expansive in
the endometrial cavity and locally infiltrates the myometrium or can expand toward
the cervical canal. The antecedent pregnancy is either a term delivery (43%), molar
(39%), abortion in 18% which may occur 1 to 18 years (mean of 6.2 years) prior to
the disease per se.[2] In this case, she had a term delivery nearly 13 years ago which makes us think whether
that pregnancy triggered the malignant transformation or is there any other reason
or source for development of this tumor. However, antecedent pregnancy > 4 years is
a poor prognostic factor triggering us to treat her with multiagent chemotherapy following
surgery.
Elevated β-hCG is seen in 69% of cases and the levels are mostly < 2,500 mIU/mL unlike
in choriocarcinoma where it is very high (>10,000 mIU/mL).[3] There have been few cases reported where the β-hCG levels were normal,[4] and it becomes difficult to use it for follow-up unlike in choriocarcinoma. The
diagnosis of ETT is based on microscopy and IHC. Microscopically, tumor cells appear
uniformly mononucleated chorionic type intermediate trophoblasts with round nuclei
and eosinophilic cytoplasm and grow in nests. A distinct hyaline-like material and
necrosis can also be noted with no significant vascular invasion. ETT has a diffuse
expression for markers such as CK/CK 18, epithelial membrane antigen, and P63. It
has focal or patchy expression for hCG, human placental lactogen (hPL), and melanoma
cell adhesion molecule (MEL-CAM) (CD146). It is positive for inhibin in 20 to 80%.[5] In this case, it was positive for P63, CK/CK 18, and inhibin. The mitotic index
varies from 0 to 9 mitosis/hpf. In this case, it was 4 mitosis/hpf. High mitotic index
suggests an aggressive tumor. The mean Ki-67 index in ETT is 17.7 + 4.5.[5]
The differential diagnosis for ETT includes choriocarcinoma, PSTT, PSN, SCC of the
cervix, and epithelioid malignant smooth muscle tumor (ESMT). It is easy to differentiate
choriocarcinoma as it has both cytotrophoblast and syncytiotrophoblast. PSTT is very
infiltrative growth, with prominent vascular invasion, and has larger implantation
type ITCs. IHC differentiates PSTT from ETT as PSTT is diffusely positive to hPL,
MEL-CAM (CD146) and negative to P63. ETT can be misdiagnosed as SCC of the cervix
especially when ETT is located at the cervix and ETT's hyaline-like matrix and necrotic
debris can resemble keratin present in the SCC of the cervix. IHC helps in distinguishing
as inhibin and CK 18 are positive in ETT but not in the SCC of the cervix. Ki-67 proliferative index is usually 10 to 25% in ETT, whereas it is high (>50%) in
choriocarcinoma and in SCC of the cervix. In our case, it was 20%. In ESMT, smooth
muscle markers will be positive. There are cases where ETT was misdiagnosed as stage
IIIB cancer of the cervix and treated with radiotherapy[6] with no good response to the treatment and also as choriocarcinoma which was treated
with only chemotherapy (without surgery) without any positive response.[7] Hence, one should be very vigilant while diagnosing ETT.
Surgery is the preferred treatment as ETT is more chemoresistant than choriocarcinoma.
The standard treatment includes total hysterectomy for early-stage disease and resection
of metastatic lesions if feasible followed by multiagent chemotherapy in metastatic
disease only. Patients with isolated lung lesion had better outcome with excision,
although they were classified as stage III. For stage I disease with antecedent pregnancy > 48
months or persistent high β-hCG levels and any stage with metastatic disease postadjuvant
platinum-based chemotherapy, either EMA/CO or etoposide, methotrexate, actinomycin-D,
etoposide, cisplatin (EMA/EP) is recommended.[8] In this case, she had certain risk factors such as her prior gestational event was
13 years back, age >40 years, and since bladder invasion was noted and margins were
not free, we decided to go for multiagent chemotherapy to prevent a recurrence. In
a case reported earlier in 2015, a 47-year-old woman with menopausal status and an
antecedent pregnancy 16 years back was treated with only surgery and she had a recurrence
4 years later though her β-hCG levels were low following surgery.[5]
Liu et al[1] did a retrospective study on 31 patients and noted stages II to IV, >3 metastatic
lesions, and chemotherapy treatment without surgery were associated with adverse recurrence-free
survival. FIGO anatomical stage is a significant prognostic factor for ETT. Combined
surgery with multiagent chemotherapy is required in metastatic disease or localized
disease with persistently positive β-hCG after surgery or if surgery is unfeasible.
The preferred chemotherapy is EMA/EP or EMA/CO.
Yang et al revealed univariate analysis showed only stage IV as the only risk factor
for poor overall survival rate. In multivariate analysis, an antecedent pregnancy
of >120 months, stage IV disease, metastatic disease, and beta-hCG >1,000 IU/L were
significantly associated with poor disease-free interval, and it was suggested to
keep a close watch for recurrence. In this study, certain immune checkpoints were
also looked for such as programmed death (PD)-L1, B7-H3, and CD105, and these were
detected 100% in ETT cases, where PD-L2 and V-domain immunoglobulin suppressor of
T-cell activation were detected in 82%, B7-H6 was seen in 18%, and B7-H4 was not detected
at all. New therapeutic targets are required to treat nonoperable patients with metastatic
chemoresistant diseases. Pembrolizumab (a humanized monoclonal antibody against PD-1)
was effective in chemoresistant GTN. The use of immunotherapy and antiangiogenic treatment
are upcoming options even in patients with ETT.[9]
Metastatic disease is seen in 25 to 42% of cases. Metastasis can occur in lung (commonest),
liver, brain, small bowel, vagina, and pelvic lymph nodes. Mortality is seen in > 10%.
The main cause of early death (which can occur < 4 weeks from diagnosis) may be mainly
due to hemorrhage from metastatic lesions or because of tumor destruction following
administration of full-dose chemotherapy.[8]
Every ETT case needs to be reported to understand this unusual disease so that we
can establish a proper means of diagnosis and management.
Conclusion
ETT is a rare and aggressive tumor that can have diverse presentations. Because of
limited knowledge of ETT, diagnosis and management remain challenging and can lead
to mismanagement and delay in appropriate treatment. Diagnosis is made on morphological
grounds, so the pathologists play an important role to detect the disease. This case
highlights that ETT can occur in postmenopausal, with no recent gestational event
and with low β-hCG levels.
