1 review Primary pulmonary choriocarcinoma Ziga Snoj, Igor Kocijancic, Erik Skof 1 Institute of Radiology, University Medical Centre, Ljubljana, Slovenia 2 Institute of Oncology, Ljubljana, Slovenia Radiol Oncol 2017; 51(1): 1-7. Received 18 March 2015 Accepted 20 May 2016 Correspondence to: Erik Škof, M.D., Ph.D., Institute of Oncology Ljubljana, Zaloška 2, SI-1000 Ljubljana, Slovenia. Phone: +386 5879 284; Fax: +386 5879 400; E-mail: eskof@onko-i.si Disclosure: No potential conflicts of interest were disclosed. Background. The aim of the study was to establish whether there are different clinical entities of primary pulmonary choriocarcinoma (PPC) that deserve different diagnostic approach and the most optimal treatment. Patients and methods. A systematic review with PubMed search was conducted to identify studies that reported cases of PPC. The eligibility criteria were histological diagnosis of pulmonary choriocarcinoma and thorough examina- tion of the reproductive organs to exclude potential primary choriocarcinoma in the gonads. Furthermore, to illustrate the review we additionally present a patient referred at our institution. Results. 55 cases (17 men) were included in the review with a median age of 34 years. Women with the history of gestational event showed better survival outcome than women without the history of gestational event. Patients treated with combined modality treatment (surgery and chemotherapy) survived longer than the patients without combined modality treatment. Furthermore, multivariate analysis of prognostic factors showed that the combined modality treatment had independent prognostic significance. Size of the tumour showed significant prognostic influ- ence in univariate and multivariate analysis. Conclusions. PPC is an extreme rarity with variable clinical characteristics and outcome. It is important to capture and treat patients in the early stages of the disease. Women with the history of gestational event may show better survival, therefore genetic examination could help us to predict patient’s prognosis. Surgery followed by adjuvant chemotherapy appears to represent the best treatment for PPC. Key words: choriocarcinoma; pulmonary tumour; gestational event Introduction Choriocarcinoma is a germ cell tumour contain- ing syncytiotrophoblastic cells and secreting hu- man chorionic gonadotropin (hCG) hormone. Gestational choriocarcinoma originating in gonads frequently metastasizes to the lungs, but primary choriocarcinoma originating in the lung is a very rare entity. Primary extragenital choriocarcinoma most often arises in retroperitoneum, mediastinum and intracranially. The mechanism of development of a primary pulmonary choriocarcinoma (PPC) is poorly un- derstood. In the literature several theories have been postulated to explain the development of PPC: metastasis from primary gonadal choriocar- cinoma that regressed spontaneously; origin from trophoblastic embolus related to gestational event after long period of latency; origin from retained primordial germ cells that migrate abnormally during embryogenesis; or a lung cancer that devel- ops originally as non-trophoblastic neoplasm and later dedifferentiates.1-5 Lately a genetical examination helped to dis- criminate between gestational and nongestational origin of PPC. Maesta et al. proved with genetical examination that the PPC in both of their cases was of gestational origin.6 On the other hand, Vegh et al. excluded gestational origin with genetical ex- amination, despite the patient had the history of gestational event.7 PPC is a highly malignant intrapulmonary tu- mour with notoriously poor prognosis. Early di- agnosis with optimal management is an impor- Radiol Oncol 2017; 51(1): 1-7. doi:10.1515/raon-2016-0038 Radiol Oncol 2017; 51(1): 1-7. Snoj Z et al. / Primary pulmonary choriocarcinoma2 tant goal, since patients captured in early stages of the disease have higher survival rate.8 There is no standardized treatment for PPC. PPC grows rapidly and has high propensity to disseminate to other organs, such as bone, liver, brain, spleen and contralateral lung.4 Due to undifferentiated nature of malignancy, PPC has poor response to radia- tion treatment.9 The most appropriate regimen for chemotherapy seems to be BEP (bleomycin, meth- otrexate and cisplatin) or EMA-CO (etoposide, methotrexate, actinomycin D, cyclophospamide and vincristine).1,6,7,8,10 Despite the absence of rand- omized trials to prove its superiority, the combina- tion of EMA-CO has become the preferred regimen for initial treatment of high-risk gestational troph- oblastic disease in most countries.11 The aim of the article was to establish whether there are different clinical entities of PPC that de- served different diagnostic and therapeutic ap- proach. Furthermore, to illustrate the review we additionally present a patient referred to our insti- tution. In order to elucidate clinical characteristics and to determine optimal way of management of this rare neoplasm we analysed our patient togeth- er with other 54 reported cases. Patients and methods All published cases of PPC were collected with a PubMed search with the key word ‘primary pulmo- nary choriocarcinoma’ and the key word ‘solitary pulmonary choriocarcinoma’ that were published in English literature. The eligibility criteria were histological diagnosis of choriocarcinoma of the pulmonary tumour and thorough examination of reproductive organs to exclude potential primary choriocarcinoma in the gonads. Differences be- tween patients groups according to gender were es- timated using nonparametric Mann-Whitney test. Probabilities of survival were estimated using the Kaplan-Meier method and differences between pa- tient groups were evaluated with the log-rank test. Prognostic factors were analysed using the Cox pro- portional hazard model. Reported values are two- sided. Statistical significance was set at p < 0.05. The patient A 35 year old woman complaining of severe right sided chest pain was admitted to our hospital. The patient had three normal term deliveries in the past 15 years and three spontaneous abortions in the past year. The chest radiograph showed a round opacity in the right lungs. A computed to- mographic scan (CT) of the chest revealed the pres- ence of 6.4 x 5.4 x 5.9 cm pulmonary mass in the right lower lobe (Figure 1A). Transthoracic needle biopsy was performed and diagnosis of poorly dif- ferentiated giant cell carcinoma (GCC) was made. To exclude additional masses FDG-PET study was performed (Figure 1B). FDG accumulation in the pulmonary mass was low, maximum standardized uptake value (SUVmax) was 2.7, and only in the periphery of the mass. No other abnormal accumu- lation was detected in whole body including pelvic cavity. During hospitalization the patient’s condi- tion progresively worsened with depleting levels of hematocrit, hemoglobin and platelets. Urgent right sided bilobectomy with pericard excision was performed. Histopathologic workup of excised tumour showed poorly differentiated carcinoma with trophoblast differentiation, most consistent with choriocarcinoma. Excised nodes showed no tumour infiltration. Four weeks after surgery the patient was ad- mitted to our hospital to start chemotherapeutical treatment. In these four weeks the patient had two episodes of epileptical seizures. CT and MRI of the head showed 1 cm intracerebral metastasis with surrounding edema (Figure 1C). FIGURE 1. (A) A computed tomographic scan of the chest showing 6.4 x 5.4 x 5.9 cm pulmonary mass in right lower lobe. (B) FDG-PET study showing FDG accumulation in the pulmonary mass in the right lower lobe with no other abnormal accumulation found in whole body including pelvic cavity. (C) CT of the head showing 1 cm intracerebral mass with surrounding oedema. A B C Radiol Oncol 2017; 51(1): 1-7. Snoj Z et al. / Primary pulmonary choriocarcinoma 3 The patient began EMA-CO regimen chemo- therapy with high dosage methotrexate. At the start of the chemotherapy plasma hCG levels were 169396 IU/L, on eighth day fell to 20883 IU/L and after three months (4 cycles of chemotherapy) the plasma hCG levels fell within normal range. Patient underwent stereotactic radiotherapy of cerebral metastasis with dose 1 x 25 Gy after the fourth cycle and afterwards received two addition- al cycles of EMA-CO regimen with standard dose of metotrexate. To completely rule out the origin of the tumour in reproductive tract the vaginal total hysterectomy with bilateral salpingoectomy was performed after 6 cycles of chemotherapy and his- topathological examination was negative. According to FIGO clinical and prognostic stag- ing patient had stage IV disease with high-risk score.12 Brain MRI was performed 7 months after stereotactic radiotherapy and showed 3 mm re- sidual mass with no surrounding edema. Patient is on regular follow-up and is still on therapy with levetiracetam and dalteparin without evidence of relapse at 12 months following surgery. The patient was treated according to the Helsinki Declaration. She gave a written informed consent before treatment to use her clinical data for research. Results Patients We searched the literature with a PubMed search to establish characteristics of PPC using criteria de- scribed in Patients and methods. A review of the literature in English revealed 54 cases with previ- ous report of primary choriocarcinoma originating in the lung.1-10,13-15,17-44 The patient described in the present paper was analysed with other 54 reported cases. The profiles of the patients are summarized in Table 1; 17 men and 38 women were included with a median age of 34 years (range 0.3 to 77). At the time of discovery 47 patients (85%) produced symptoms, including persistent cough (40%), dysp- nea (31%), hemoptysis (25%) and chest pain (20%). At presentation 8 tumours were asymptomatic. A few of the women have presented with hormonal problems such as amenorrhea or vaginal bleeding. In men, signs of feminisation such as gynecomastia have been observed but are uncommon. Correlation between gender and clinicopathological factors We analysed the relationship between gender and other clinicopathological features in patients with PPC (Table 2). Men were older than women (p = 0.000). Men had the history of smoking more often than women (p = 0.000). No statistically significant difference between genders was observed for loca- tion, size, presence of metastases, history of haem- optysis or treatment. Survival Only 47 cases (16 men and 31 women) reported treatment outcome. The median survival time was TABLE 1. Primary pulmonary choriocarcinoma: Summary of reported cases No of patients 55 Gender, male/female 17/38 Median age all patients, years 34 Median age female, years 33 Median age male, years 60 Initial symptom Cough 22 Dyspnea 17 Hemoptysis 14 Chest pain 11 Asymptomatic 8 Location Right / Left lung 29/18 Right upper lobe 11 Right middle lobe 3 Right lower lobe 15 Left upper lobe 12 Left lower lobe 4 Bilateral 2 Tumor size, cm ≤ 5 23 > 5, ≤ 10 13 > 10 8 Treatment S 10 C 8 RT 3 S + C 24 S + C + RT 3 C = chemotherapy; RT = radiotherapy; S = surgery Radiol Oncol 2017; 51(1): 1-7. Snoj Z et al. / Primary pulmonary choriocarcinoma4 8 months. The review of these 47 cases showed 1-, 2-, and 5- year survival rates of 61%, 57% and 49%, respectively. Important difference (p = 0.004) in survival time between genders was observed with women showing 1-, 2-, and 5- year survival rates of 77%, 77% and 64% while men showed 1-, 2-, and 5- year survival rates of 31%, 21% and 21%, respec- tively (Figure 2A). In Table 3 univariate analysis is shown. Younger patients (< 40 years) survived longer than older pa- tients (≥ 40 years), (p = 0.009). Patients with smaller tumours (< 5cm) survived longer than patients with larger tumours (≥ 5cm), (p = 0.000). Survival of patients without metastases at presentation was longer than for patients with metastases (p = 0.000). Patients without the history of smoking survived longer than patients with the history of smoking (p = 0.001). The women were further divided into two groups according to the history of gestational events (such as abortion, pregnancy or hydatiform mole) within the time period of less than 7 years prior the admission. Women with the history of gestational event (n = 14) had better survival out- come than women without the history of gesta- tional event (n = 17), the difference was statistically significant (p = 0.040), (Figure 2B). Patients treated with combination of surgery plus chemotherapy survived longer than those treated with optimal supportive care or either chemotherapy or surgery alone (p = 0.001). Patients treated with chemothera- py only survived less than the patients treated with surgery only or combination of chemotherapy and surgery (p = 0.016). Patients treated with combina- tion of surgery and chemotherapy survived longer than patients without combination of surgery and chemotherapy (p = 0.010). Treatment with surgery demonstrated no significant prognostic influence. As shown in Table 4, multivariate analysis of prognostic factors using the Cox proportional haz- ards model showed that the treatment combin- ing surgery with chemotherapy had independent prognostic significance (p = 0.007). Furthermore, A B FIGURE 2. Kaplan-Meier survival curves. (A) Survival for all reported cases with curves showing survival for female patients was longer than for male patients (p = 0.004). (B) Survival of all reported cases with survival of men and curves showing survival of female patients with the history of gestational event was longer than for female patients without the history of gestational event (p = 0.040). TABLE 2. Differences between female and male patients primary pulmonary choriocarcinoma Characteristics Female Male p-value Age < 40 30 4 ≥ 40 9 13 0.000 Size, cm < 5 17 7 ≥ 5 12 8 0.162 Metastasis Yes 15 10 No 24 7 0.161 Smoking Yes 2 9 No 37 8 0.000 Hemoptysis Yes 13 5 No 25 11 0.780 Treatment S Yes 24 9 No 4 4 0.221 C Yes 21 10 No 7 3 0.895 S+C Yes 17 7 No 11 6 0.682 C = chemotherapy; S = surgey All patients, n = 47 All patients, n = 47 Men, n = 16 Women, n = 31 Women with positive gestational history, n = 14 Men, n = 16 Women with negative gestational history, n = 17 Radiol Oncol 2017; 51(1): 1-7. Snoj Z et al. / Primary pulmonary choriocarcinoma 5 the size of the lesion showed an independent prog- nostic significance (p = 0.008). Discussion In the present work we made a systematic review of the relevant literature. We found out that there are different clinical entities of PPC based on gen- der and reproductive history that show different survival. Furthermore, we showed it is important to capture and treat patients in the early stages of the disease. In addition we demonstrated that sur- gical treatment combined with chemotherapy is the best treatment regarding survival. Gender difference PPC occurs in women in younger ages than in men (33 vs. 60 median age), an observation already described by Umemori et al.8 Therefore, it can be derived that PPC in women is more likely to oc- cur in the reproductive period. Furthermore, there are more reported cases with women than men. Statistically significant difference in survival time between genders was observed with women show- ing better outcome. We further divided women in two groups due to the history of the gestational event within the time period of less than 7 years prior the admission. We chose the cut off of 7 years conservatively on the basis of three published cas- es with genetical examination.6,7 In the paper by Maesta et al. they present two patients with gesta- tional event within 4 years prior to PPC diagnosis and in both cases they proved it to be of gestational origin.6 In the paper by Vegh et al. the patient had the last gestational event 7 years prior to admission and with fluorescence in situ hybridization they excluded gestational origin, no paternal chromo- some was found in tissue examinated.7 Based on this assumption we considered that women with the history of gestational event less than 7 years had better survival outcome than women without such history of gestational event. Looking at aforementioned gender differen- cies, PPC seems to be of different etiology in men. Furthermore, we showed that men have a history of smoking more often than women. To support TABLE 3. Possible prognostic factors Characteristic n MST (months) 1-year survival (%) 2-year survival (%) p-value Gender Female 31 - 77.3 77.3 Male 16 4 31.3 20.8 0.004 Age < 40 29 - 75.9 58.4 ≥ 40 18 4 33.3 33.3 0.009 Size (cm) < 5 20 - 80.0 80.0 ≥ 5 16 3 25.0 0.0 0.000 Metastasis Yes 21 4 42.9 0.95 No 26 - 84.6 84.6 0.000 Smoking Yes 11 4 0.0 0.0 No 36 - 69.4 69.4 0.001 Female – gestational history Positive 14 - 69.6 69.6 Negative 16 - 56.3 56.3 0.040 Treatment S Yes 9 - 55.6 55.6 No 32 - 71.0 64.5 0.458 C Yes 7 3 28.6 28.6 No 34 - 75.8 69.9 0.016 S+C Yes 24 - 83.3 56.3 No 17 4 41.2 41.2 0.010 C = chemotherapy; MST = median survival time; S = surgery Radiol Oncol 2017; 51(1): 1-7. Snoj Z et al. / Primary pulmonary choriocarcinoma6 the theory of dedifferentiation four cases of PPC have been reported with co-existent pulmonary carcinoma.5,10,13,14 All were male patients, in three cases PPC was sinchronous and found at autopsy, in one case the PPC was metachronous arising 6 years after diagnosis of squamous carcinoma. Problematically primary pulmonary carcinomas can produce hCG. Ikura et al. reported more intense expression of hCG in PPC than in hCG producing GCC.14 Although this finding seemed to reflect the level of serum hCG the cut off point seemed to be ambigous.15 Because of the rarity and clinicopatho- logical similarity of PPC and hCG producing GCC the criteria for distinguishing them are unclear and the diagnosis is very difficult.14 Survival The survival data should be handled cautiously because of the possibility that mostly patients with good survival were reported in the literature and the rest were neglected. Nevertheless PPC is no- torious for having a poor prognosis, however, the present review shows 1-, 2-, and 5- year survival rates of 61%, 57% and 49%, which is reasonably good. Furthermore, if only female patients are ob- served the survival rates are even higher. Patients having smaller size tumour and being without me- tastases at diagnosis have higher survival rate, thus early diagnosis with optimal management is im- portant. The outcome is still worrying but in com- parison with the review article from the year 2004 by Umemori et al. where they reported 1-, 2-, and 5- year survival rates of 41%, 34%, 34% the outcome results are more promising. We noticed that the early reports of PPC had poorer outcome than the ones nowadays and that chemotherapeutical treat- ment was rarely used in the cases prior to year 1994 but if chemotherapy was used it was single modal- ity therapy. The evolvement of chemotherapeuti- cal treatment and better supportive therapy could influence the better outcomes seen in the present review, but we could not attribute the difference in survival rates to the specific factor due to the rarity and nonexistence of therapeutic guidelines. Treatment In order of finding out any relationship between treatment and survival the univariate and multivar- iate analysis of prognostic factors was carried out. Univariate analysis showed that treatment with chemotherapy only is not good choice of treatment however significant prognostic influence for com- bined treatment with surgery and chemotherapy was found. Furthermore, multivariate analysis of prognostic factors revealed that combined treat- ment with surgery and chemotherapy had inde- pendent prognostic significance. These findings are in concordance with already known facts that PPC is very aggressive disease, not just locally, but also by early spread to other organs.4 Therefore, com- bined modality treatment (surgery and chemother- apy) represents best possible way to improve sur- vival. Of course patients have to be fit enough for such aggressive treatment. No reports of extended survival were found in patients who underwent complete resection without chemotherapy. Conclusions PPC is an extreme rarity with variable clinical char- acteristics and outcome. It is important to capture and treat patients in the early stages of the disease. Women with the history of gestational event may show better survival, therefore genetic examina- tion could help us to predict patient’s prognosis. Surgery followed by adjuvant chemotherapy ap- pears to represent the best treatment for PPC. TABLE 4. Multivariate analysis of prognostic factors, Cox proportional hazards model S+C HR 95% CI p-value Yes 0.147 0.036 – 0.598 0.007 No 1 Smoking Yes 1.827 0.418–7.982 0.423 No 1 Gender Male 1.266 0.248–6.466 0.776 Female 1 Tumour size, cm ≥ 5 6.622 1.622–27.031 0.008 < 5 1 Age, years ≥ 40 0.879 0.164–4.703 0.880 < 40 1 C = chemotherapy; HR = hazard ratio; S = surgery Radiol Oncol 2017; 51(1): 1-7. Snoj Z et al. / Primary pulmonary choriocarcinoma 7 Acknowledgement We would like to thank M. Števanec for helping us with statistical analysis and Professor M. Snoj, M.D., Ph.D. for guidance with statistical interpre- tation. References 1. Serno J, Zeppernick F, Jäkel J, Schrading S, Maass N, Meinhold-Heerlein I, et al. Primary pulmonary choriocarcinoma: case report and review of the literature. Gynecol Obstet Invest 2012; 74: 171-6. 2. Maruoka Y, Abe K, Baba S, Isoda T, Matsuo Y, Kubo Y, et al. 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