Diagnosis and management of a metastatic mixed gestational trophoblastic neoplasia with synchronous primary lung cancer

Background

Gestational trophoblastic neoplasias (GTNs) are rare placental tumours that arise from aberrant fertilisation events. Subtypes of GTNs include placental site trophoblastic tumours (PSTT), epithelioid trophoblastic tumours (ETT) and choriocarcinomas.1 2 These cancers are unique among human neoplasias as the majority are highly curable even in the presence of widely metastatic disease.3 However, distinguishing between subtypes is of critical importance in informing the therapeutic approach. Namely, choriocarcinomas have the greatest risk for early haematogenous dissemination, though these are also exquisitely sensitive to chemotherapy.3–5 PSTTs and ETTs, in contrast, typically present with uterine confined disease and are relatively chemoresistant, requiring surgical intervention.3 5 Mixed GTNs are defined by the presence of two or more histological subtypes; these are rarely encountered, and to date, only 34 cases have been published in the literature.6 7 We present the case of a woman diagnosed with a mixed GTN, with a predominant component of choriocarcinoma, which was diagnosed 14 years following her last pregnancy. We discuss the challenges in diagnosis and management, both initially and in the setting of disease progression and lung metastases. We also reflect on the dilemma faced by both the patient and medical team when residual lung nodules—ultimately identified as a synchronous primary lung adenocarcinoma—remained following completion of chemotherapy and resolution of her beta-human chorionic gonadotropin (b-hCG) levels. Altogether, we demonstrate the importance of multidisciplinary care and the necessity of patient engagement in the approach to an exceptionally rare diagnosis.

Case presentation

A 50-year-old G2P2002 woman came to medical attention when she acutely developed heavy vaginal bleeding with the passage of clots. Her medical history was significant only for depression and endometriosis. She had never used tobacco products and took no medications. Her first pregnancy had been complicated by premature rupture of membranes at 15 weeks, though she carried that child to term and had a spontaneous vaginal delivery; her second pregnancy was 14 years ago and was uncomplicated. She had had an intrauterine device (IUD) placed 5 years prior to presentation and had since been amenorrheic; it was not possible to say definitively whether the patient was in menopause.

On the patient’s initial presentation, her gynaecologist performed a pelvic ultrasound with IUD removal. The ultrasound demonstrated a 4.6×3.2 cm uterine mass extending from the mid-to-lower uterine segment, as well as a calcified uterine fibroid. The presence of a heterogeneously enhancing mass in the lower uterine segment was confirmed by CT of the abdomen and pelvis. The patient’s b-hCG was found to be significantly elevated at 3704 mIU/mL. The initial endometrial biopsy showed fragments of malignant cells in a background of blood and necrotic debris (figures 1–2). Neoplastic cells were polygonal with irregular hyperchromatic nuclei and ample eosinophilic cytoplasm. There was no normal endometrial or endocervical tissue present in the specimen, and immunohistochemistry studies were positive for cytokeratin 7 and hCG. These data were suggestive of a malignant GTN though a more precise diagnosis (choriocarcinoma vs PSTT vs ETT) could not be made at the time.

Figure 1

Endometrial biopsy pathology. High-grade trophoblastic neoplasm in a background of abundant blood and fibrin (H&E, ×100).

Figure 2

Endometrial biopsy pathology. High-power view demonstrates high-grade mitotically active cells, ranging from large, multinucleated cells to others with an epithelioid appearance (H&E, ×400).

Differential diagnosis

GTNs are a group of interrelated but histologically distinct, malignant lesions that arise from the abnormal growth of placental trophoblastic cells. Subtypes include choriocarcinomas, PSTT, ETT. As noted above, distinguishing between subtypes is of critical importance in informing the therapeutic approach, and pathology is critical to making a diagnosis.

Choriocarcinomas are traditionally hCG-producing epithelial tumours characterised histologically by tissue necrosis, a high degree of vascularity and the absence of chorionic villi.1–3 PSTTs, on the other hand, stain positive for human placental lactogen (hPL), with staining for hCG positive in only a few cells. ETTs are extremely rare and are characterised by a monomorphic cellular pattern of epithelioid cells.1 2 The latter two tend to grow more slowly relatively to choriocarcinomas and are less sensitive to chemotherapy. As such, even early-stage PSTTs and ETTs often require more aggressive management upfront (eg, surgery) whereas choriocarcinomas can be managed with chemotherapy alone.1–4

Given the uncertain aetiology of our patient’s tumour on initial endometrial biopsy (and inability to definitively rule out PSTT or ETT), the team opted to debulk surgically, both as a first step in treatment and to assist with definitive diagnosis. The patient underwent laparoscopic total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH-BSO) and excision of pelvic lymph nodes. Within this specimen, the tumour was noted to be 5.0×4.0×2.2 cm and occupied the anterior and posterior uterine walls. It had invaded the myometrium with a pushing border (figure 3). Extensive tumour necrosis was present though all pelvic lymph nodes were negative.

Figure 3

Hysterectomy specimen pathology. Frankly malignant tumour with myometrial invasion (H&E, ×40).

Further histological examination of the uterus proved quite challenging. On one hand, the extensive haemorrhage and necrosis, coupled with prominent spindling and pleomorphic nucleoli in the setting of diffuse and intense staining for hCG, were enough to characterise the cancer as a choriocarcinoma (figures 4–5). However, sections of the tumour also exhibited well-defined splitting and splaying of the smooth muscle bundles in the myometrium by trophoblasts that were more consistent with PSTT (figure 6). In addition, these sections were strongly immunopositive for hPL and mucin-4 (MUC-4), further substantiating this hypothesis. Finally, in a single section of the tumour, there was an area defined by trophoblastic cells in an epithelioid growth pattern, which stained diffusely for p63, highly suggestive of ETT. Ultimately, the medical team settled on a final diagnosis of a high-grade gestational trophoblastic tumour, largely with features of choriocarcinoma but with minor components of PSTT and ETT.

Figure 4

Hysterectomy specimen pathology. Trimorphic population of syncytiotrophoblasts, cytotrophoblasts and intermediate trophoblasts, characteristic of choriocarcinoma (H&E, ×200).

Figure 5

Hysterectomy specimen pathology. Spindled and pleomorphic tumour cells with easily identifiable mitotic figures (H&E, ×200).

Figure 6

Hysterectomy specimen pathology. Minor component of placental site trophoblastic tumour containing trophoblasts with abundant eosinophilic cytoplasm, which splay smooth muscle fibres as they invade the myometrium (H&E, ×200).

Initial outcome and follow-up

Following her TAH-BSO, the patient was followed closely with serial hCG levels. The patient’s hCG declined during postoperative recovery for 4 weeks. Unfortunately, it then began to plateau and, on postoperative day 39, rose from 67 IU/mL to 113 IU/mL, at which point the patient was restaged.

A CT chest showed numerous bilateral pulmonary nodules. The patient had had interval development of a 1.4 cm nodular opacity at the right lung base, a 1.2 cm prefissural nodular opacity in the left lower lobe and additional subcentimeter nodules in all lung fields. A brain MRI was performed that did not show evidence of central nervous system involvement. Additional PET imaging was not pursued given high concordance of PET scan results with CT imaging in patients with GTN.8 Based on the International Federation of Gynaecologic Oncology staging system and WHO Risk Scoring System for GTN, she was restaged as stage III: 11 disease.

Treatment

Given the progression of her disease and high-risk score, the patient was subsequently initiated on combination chemotherapy consisting of etoposide, methotrexate and actinomycin-D alternating every 2 weeks with cyclophosphamide and vincristine. She suffered greatly both physically and emotionally during treatment. Her most prominent side effect was nausea, which required prolonged hospital stays for hydration and resulted in severe depression, manifested by a near-complete withdrawal from her family. Indeed, it was only with significant support from her team psychologist and social worker that the patient completed six cycles of treatment and achieved normalisation of b-hCG levels.

Imaging is not routinely performed in a patient with GTN who has had a serological response to treatment. Rather, it is reserved for the end of therapy or if complications arise.9 However, given the mixed GTN, presence of pulmonary nodules and concern for a chemoresistant subtype, post-treatment CT imaging was pursued that showed only partial resolution of patient’s lung findings. Of greatest concern, we identified a 6 mm nodule in the right lower lobe that had remained stable. This was reviewed at a Multidisciplinary Gynaecologic Oncology Tumour Conference where there was a lack of consensus on next steps; some clinicians favoured surveillance with repeat imaging in 2–3 months (given the normalisation of her tumour markers); others favoured surgical resection of residual disease, given the concern for PSTT or ETT, which are both chemoresistant.

Faced with equipoise, the patient opted to proceed with right thoracoscopy and wedge resection of two segments within the right lower lobe, as well as a singular segment in the right upper lobe. Final pathology from the superior segment of the right lower lobe revealed a 9 mm invasive adenocarcinoma consistent with a primary lung adenocarcinoma (thyroid transcription factor-1 (TTF1) positive, napsin A positive) with clear margins and no evidence of lymphovascular space invasion (figure 7). It did not resemble the trophoblastic tumour. The new primary was acinar predominant (45%), with papillary (40%), lepidic (10%) and micropapillary (5%) components. The patient was ultimately staged with pT1a lung cancer. Pathology from the remaining segments demonstrated parenchymal fibrosis with associated inflammatory cells that were favoured to represent treated tumour, with no evidence of malignant cells. After discussion with thoracic oncology and per National Comprehensive Cancer Network (NCCN) guidelines, no further surgical or adjuvant chemotherapy was recommended for the patient’s stage 1 lung adenocarcinoma, and she continued to undergo CT imaging biannually to monitor for disease recurrence.

Figure 7

Lung resection pathology. Right lower lobe superior segment demonstrating primary lung adenocarcinoma (H&E, ×100).

Final outcome and follow-up

Now 2 years postchemotherapy and surgery, the patient remains free of disease. Her hCG remains under 3 IU/mL and repeat chest CT as part of surveillance for her lung cancer has shown no evidence of relapse.