| Abstract|| |
One of the very rare forms of gestational neoplastic diseases is the malignant placental site trophoblastic tumor. Due to its rarity, the data regarding its diagnosis and management are limited. The prognosis of this tumor is unpredictable with potential malignant behavior and metastasis. We report a case of malignant placental site trophoblastic tumor with multiple metastatic deposits in the ovaries, lungs, kidneys, adrenals, and pancreas. The patient was treated by surgery and an extensive subsequent chemotherapy. The disease progressed, and the patient died 17 months after diagnosis.
Keywords: Malignant, ovary, placental site, trophoblasts, uterus
|How to cite this article:|
Fathaddin AA, Arafah MA. A malignant placental site trophoblastic tumor of the uterus with multiple metastases: A case report of a rare tumor showing an aggressive behavior. Indian J Pathol Microbiol 2019;62:142-5
|How to cite this URL:|
Fathaddin AA, Arafah MA. A malignant placental site trophoblastic tumor of the uterus with multiple metastases: A case report of a rare tumor showing an aggressive behavior. Indian J Pathol Microbiol [serial online] 2019 [cited 2019 Apr 24];62:142-5. Available from: http://www.ijpmonline.org/text.asp?2019/62/1/142/251256
| Introduction|| |
Gestational trophoblastic diseases (GTDs) are a group of diseases that are related to normal or abnormal pregnancies. They include hydatidiform moles (complete and partial), invasive moles, benign lesion arising from intermediate trophoblasts including an exaggerated placental site and placental site nodules, and tumors arising from the same type of cells including placental site trophoblastic tumors (PSTTs) and epithelioid trophoblastic tumors (ETTs), in addition to choriocarcinoma which arises from the abnormal proliferation of both cytotrophoblasts and syncytiotrophoblasts.
PSTT is rare and presents 1%–2% of all GTDs and <0.25% of gestational trophoblastic neoplasia (GTN)., It was first described by Kurman and Scully in 1976 as trophoblastic pseudotumor. Few years later, it was recognized as a neoplastic entity with possible malignant behavior and named as placental trophoblastic tumor. It can occur many years following a pregnancy of any outcome. Unlike other types of GTDs, it produces less amount of beta-human chorionic gonadotropin (β-hCG) and it is less sensitive to chemotherapy. Because of its rare incidence, the etiology of PSTT is not yet fully understood, the data are limited regarding its management, and the prognosis of this tumor is quite unpredictable. Approximately 300 cases have been reported in the English literature. Metastasis at the time of presentation has been variably reported in different studies and ranges from 10% to 35%.,,, Kidneys and adrenals are very uncommon sites of extrapulmonary metastasis.,
| Case Report|| |
We report a case of chemoresistant malignant placental site trophoblastic tumor with an aggressive behavior and multiple metastases in a 43-year old female. The patient died 17 months following her initial presentation. After the diagnosis was made, an informed consent to write this paper was obtained from the patient.
The patient presented to a private hospital with a massive vaginal bleeding which was managed by a subtotal hysterectomy. A year later, she was referred to our hospital because of persistent high serum levels of β-hCG. The patient has three children; all delivered vaginally with no complications. She has no significant medical or surgical history. On presentation, her serum level of β-hCG was 3,189 IU/L. A computed tomography scan (CT scan) of the chest, abdomen, and pelvis was done and showed a thickened cervical stump with a mass-like lesion invading the right distal ureter and inseparable from the urinary bladder and rectal wall. Three lung nodules were also seen, the largest measured 4 mm in greatest dimension. The histopathology slides and report from the private hospital were requested for review. The diagnosis from the refereeing laboratory was features of a malignant cellular neoplasm.
Microscopic examination of the formalin-fixed, paraffin-embedded and hematoxylin, and eosin-stained tissue sections revealed sheets of large polygonal cells with eosinophilic cytoplasm and marked nuclear pleomorphism [Figure 1]a. Some of the nuclei showed anaplastic features [Figure 1]b. Abundant mitotic figures were seen including atypical ones [Figure 1]c. There were tumor necrosis and vascular invasion with foci of fibrinoid material deposition [Figure 1]d. Multinucleated syncytiotrophoblasts were not seen. The tumor was invading more than 50% of the myometrial thickness. Immunohistochemical stains showed that tumor cells were strongly and diffusely positive for human placental lactogen (hPL) and cytokeratin 8/18 [Figure 2]a and [Figure 2]b, respectively]. hCG immunostain showed focal positivity [Figure 2]c. P63 immunostain was negative. Ki-67 proliferation index was more than 50% [Figure 2]d.
|Figure 1: (a) Large tumor cells with eosinophilic cytoplasm and pleomorphic nuclei (H and E, ×100). (b) Nuclear anaplasia was noted (H and E, ×200). (c) Mitoses including atypical ones were frequent (H and E, ×400). (d) Vascular invasion was also present (H and E, ×400)|
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|Figure 2: Immunohistochemical stains showed tumor cells strongly and diffusely positive to (a) Human placental lactogen (×100) and (b) cytokeratin 8/18, (×100). (c) Human chorionic gonadotropin immunostain showed focal positivity (human chorionic gonadotropin, ×100), and (d) Ki-67 proliferation index was more than 50% (Ki-67, ×200)|
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Based on these findings, a diagnosis of a malignant placental site trophoblastic tumor was made.
Further clinical evaluation
The patient was started on EMA/CO chemotherapy regimen (etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine). After 7 cycles, β-hCG levels dropped to 83 IU/L. A repeated CT scan showed a significant regression in the cervical stump thickness with an enlargement of the right ovary. The patient's case was discussed in a tumor board meeting and surgery was decided. Intraoperatively, the mass was extending into the pelvic sidewall with a secondary involvement of the right ovary. Debulking and a right salpingo-oophorectomy were done. Histopathological examination of the sample showed involvement of the ovary and fallopian tube by the same tumor.
On follow-up, the patient's serum levels of β-hCG were still persistently low. She was admitted for a second-line chemotherapy (paclitaxel, ifosfamide, and cisplatin).
Restaging CT scan showed several new metastatic deposits involving the pancreas, adrenal glands, left kidney [Figure 3], lungs, liver, and brain.
|Figure 3: Computed tomography scan of the abdomen and pelvis shows metastatic deposits in both adrenals (blue arrows) and left kidney (black arrow)|
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During her admission, the patient developed fever and neutropenia with a productive cough and yellowish sputum. A bronchoalveolar lavage revealed Aspergillus flavus for which the patient was started on voriconazole. The patient subsequently developed a septic shock and died 17 months after her initial presentation to our institution.
| Discussion|| |
GTDs arise from an abnormal proliferation of placental trophoblasts, which encompass syncytiotrophoblast, cytotrophoblast, and intermediate trophoblast. PSTT arises from implantation site intermediate trophoblasts.,
PSTT typically occurs in reproductive-aged females with an average age of 33 years (range: 28–47 years). Most patients present after full-term deliveries, others present following therapeutic or spontaneous abortions with few cases following a term or a molar pregnancy., The most common symptoms at the time of initial presentation, in order of frequency, are irregular per vaginal bleeding, amenorrhea, and a palpable abdominal mass. Other presenting symptoms include uterine rupture and nephrotic syndrome., The reported percentage of Stage IV disease (extrapulmonary metastasis) is variable in the literature and was reported to be 10%, 31%, and 35% in different studies.,, The brain, liver, and spine were reported sites of distant metastasis as shown in the study by Hyman et al. However, the bowel, adrenals, kidneys, and the pancreas were not among the common sites of extrapulmonary metastasis. The β-hCG serum levels are variable, but they are often lower than those seen in cases of choriocarcinoma. The median β-hCG serum level at diagnosis is 132 IU/L (range: 2–19,285 IU/L). However, β-hCG serum levels were reported to be normal in the earlier stages of PSTT in some cases.
Our patient is a 43-year-old female who is above the average age at diagnosis but still within the age range. She presented with abnormal vaginal bleeding. Multiple metastases to the brain, lungs, kidneys, adrenals, and pancreas developed later in the course of her disease with an initial serum β-hCG level of 3189 IU/L.
Histopathologically, PSTT consists of proliferating sheets of intermediate trophoblasts with a prominent predilection to invade blood vessels. The cells are polygonal with large atypical nuclei. Neither syncytiotrophoblasts nor chorionic villi are seen. In comparison to choriocarcinoma, tumor cells in PSTT show less necrosis and hemorrhage while having a higher tendency to spread through lymphatics., Immunohistochemical stains show a strong positive staining for hPL (negative in ETT) and a weak focal positive staining for hCG (which differentiates it from choriocarcinoma in which hCG is usually diffusely positive). P63 is typically negative (positive in ETT). Ki-67 proliferation index stains 8%–20% of tumor cells., The prognosis of PSTT is highly variable with no consensus on the prognostic factors that may predict an aggressive behavior. Despite that the WHO and Féderation Internationale de Gynécologie et d'Obstétrique (FIGO) scoring systems for the treatment and prognosis of choriocarcinoma and invasive moles are common in practice, these guidelines have not been widely validated for the management of malignant PSTT. Among the published literature, it is suggested that stage is the most important prognostic factor. The anatomic FIGO staging system defines stage based on the extension of tumor, i.e., Stage I are tumors confined to the uterus, while an extension to the adnexa or vagina qualifies for Stage II. Stages III and IV are reserved metastatic tumor to the lungs (Stage III) and extrapulmonary sites (Stage IV). Other suggested prognostic and predictive factors include time since last pregnancy, age ≥35 years, gravidity >2, tumor size ≥30 mm, and myometrial invasion depth of more than half of the myometrial thickness., Regarding treatment, in contrast to choriocarcinoma, surgery is considered the first-line treatment in patients with PSTT because of its relative chemoresistance. The aim of surgery is to remove the tumor and related lesions, including a total hysterectomy with or without a bilateral salpingo-oophorectomy. Total abdominal hysterectomy is an effective treatment option in most patients with localized tumors. Tumor reductive surgery can be performed for locally advanced or metastatic diseases.
A single-agent methotrexate or actinomycin D protocols have been reported to achieve cure in almost all patients.,,,,, On the other hand, 5-day dosage schedules of methotrexate and actinomycin D are recommended for metastatic low-risk tumors (Stages II and III). Patients with high-risk metastatic diseases (Stage IV) are usually managed by a combination of chemotherapy with different regimens, for example, etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine (EMA/CO), which appear to give successful results. Adjuvant radiation therapy may have a role as shown in the published literature.,,,,,
Although patients with nonpulmonary metastasis (Stage IV) require an aggressive course of treatment, dose-dense platinum-containing multidrug chemotherapy and targeted surgery can achieve cure in patients with pulmonary metastasis as shown by Hyman et al. In their study, Hyman et al. reported that 83% of Stage IV patients died of metastatic PSTT despite aggressive chemotherapy with a median survival of 12.6 months.
Our patient underwent surgery and extensive combined chemotherapy (EMA-CO). She died 17 months after her presentation to our hospital.
Regarding tumor's genetics, a study found an absence of Y-chromosome in 20 cases of PSTT with a haploid pair of X-chromosomes. It was suggested that the paternal X-chromosome has a functional role in the pathogenesis of PSTT although it is still unclear how this chromosome contributes in the tumor proliferation. Karyotype of PSTT is diploid in most of the cases, but few cases of tetraploidy have been reported.
| Conclusion|| |
PSTT is the rarest form of GTN with an unpredictable behavior and no definitive prognostic scale or a therapeutic protocol. In addition, it can be a diagnostic challenge for both clinicians and pathologists. PSTT is relatively chemoresistant, hence the importance of recognizing and distinguishing it from other GTN. The diagnosis should be considered clinically in patients with persistent or increased levels of serum β-hCG. Pathologists should also consider PSTT in the differential diagnosis of any poorly differentiated tumor of the uterus or ovaries. Immunohistochemical stains are helpful in reaching the correct diagnosis in most cases. Surgery has the leading role in treatment, with combined chemotherapy in advanced cases.
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Conflicts of interest
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Amany Abdulgader Fathaddin
Department of Pathology and Laboratory Medicine, College of Medicine, King Saud University and King Khalid University Hospital, P. O. Box 2925, Riyadh 11461
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]