Classic biphasic pulmonary blastoma: A case report and review of the literature

Classic biphasic pulmonary blastoma: A case report and review of the literature

Lung Cancer 73 (2011) 127–132 Contents lists available at ScienceDirect Lung Cancer journal homepage: www.elsevier.com/locate/lungcan Review Class...

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Lung Cancer 73 (2011) 127–132

Contents lists available at ScienceDirect

Lung Cancer journal homepage: www.elsevier.com/locate/lungcan

Review

Classic biphasic pulmonary blastoma: A case report and review of the literature S. Van Loo a,∗ , E. Boeykens b , I. Stappaerts b , R. Rutsaert a a b

Department of Thoracic and Vascular Surgery, Sint Vincentiusziekenhuis, Sint Vincentiusstraat 20, 2018 Antwerpen, Belgium Department of Pneumology, Sint Vincentiusziekenhuis, Sint Vincentiusstraat 20, 2018 Antwerpen, Belgium

a r t i c l e

i n f o

Article history: Received 3 January 2011 Received in revised form 8 March 2011 Accepted 23 March 2011 Keywords: Biphasic pulmonary blastoma Lung tumor Solitary nodule Well-differentiated fetal adenocarcinoma Review Chemotherapy

a b s t r a c t Pulmonary blastomas are rare malignant tumors, comprising only 0.25–0.5% of all malignant lung neoplasms. Pulmonary blastomas are subdivided in three categories: well-differentiated fetal adenocarcinoma (WDFA), classic biphasic pulmonary blastoma (CBPB) and pleuropulmonary blastoma (PPB), which is currently regarded as a separate entity. The majority of patients with CBPB and WDFA are adults with an average age of 43 years. Tobacco use is identified as a causative agent. Symptomatology varies from asymptomatic (40%) to symptoms of a non-specific pulmonary disease. The most common roentgenologic pattern is a large peripheral nodule. The treatment of choice is surgical excision. The efficacy of adjuvant chemotherapy and radiotherapy is not yet established. The prognosis of pulmonary blastoma is very poor; overall five-year survival is 16%. WDFA appears to have a better prognosis. Adverse prognostic factors are biphasic type, tumor recurrence, metastasis at initial presentation, gross size of the tumor (>5 cm) and lymph node metastasis. On the basis of the available literature, an initial aggressive treatment that includes surgery and, wherever possible, postoperative chemotherapy and radiotherapy could be useful to prolong survival in patients with this rare lung neoplasm. We present a case of classic biphasic pulmonary blastoma in a 77-year old male and review the literature. © 2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Pulmonary blastoma is a rare and aggressive malignant neoplasm. It consists of three subgroups: one biphasic type, classic biphasic pulmonary blastoma (CBPB) and two monophasic types, well-differentiated fetal adenocarcinoma (WDFA) and pleuropulmonary blastoma (PPB). PPB usually develops in the first decade of life and has been recognized as a distinct clinico-pathological entity. Although histological similarities exist between CBPB and WDFA, reason why they are both classified as pulmonary blastomas, they have distinct clinical and prognostic features. The best treatment of pulmonary blastoma is surgery in the early stages of the disease. Adjunctive therapy is still controversial because of lack of data. The literature on the this rare disorder is reviewed. 2. Case report A 77-year-old male presented with a 2 week history of haemoptysis and shortness of breath. The patient had a history of tobacco use, cumulative 15 pack years. Chest X-ray revealed a well-defined mass located posterior in the right lung. Computed tomography

∗ Corresponding author. Tel.: +32 494 16 86 09; fax: +32 9346 70 27. E-mail addresses: [email protected], [email protected] (S. Van Loo). 0169-5002/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2011.03.018

(CT) confirmed a mass of approximately 5 cm in diameter in the right upper lobe (Fig. 1). Anemia, high C-reactive protein and a high erythrocyte sedimentation rate were noted. Bronchial biopsy revealed a malignant mesenchymal tumor, possibly sarcoma. Immunohistological investigation was negative for cytokeratin broad spectrum, neuron-specific enolase (NSE) and desmin. On the other hand ␣-smooth muscle actin was expressed. Systemic evaluation by positron emission tomography (PET) scan and magnetic resonance imaging (MRI) of the brain did not show any evidence of metastases. The patient underwent a right upper lobectomy with mediastinal lymph node dissection. Due to the proximity of the tumor, the apex of the lower lobe was also resected. The postoperative course was complicated by a mild pneumonia. The patient was discharged on the13th postoperative day. Pathology of the resected specimen showed a biphasic tumor with a diameter of 6 cm, consisting of both epithelial and sarcomatous components. Obviously malignant epithelial or synovia-like cells formed irregular glands and lined larger cavities. These malignant glandular structures and cavities were surrounded by malignant sarcomatous stroma and therefore the preliminary diagnosis of biphasic synoviosarcoma was made. However, further molecular investigation was negative on synovial sarcoma translocation (SYT). Re-evaluation of the lesion showed a biphasic tumor with a large undifferentiated stroma and branching epithelial tubuli (Fig. 2). The overall appearances were consistent with a biphasic pulmonary blastoma. There was no light microscopic evi-

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Fig. 1. On CT, pulmonary blastoma is seen as a mixed solid and cystic lesion with variable contrast enhancement and a necrotic centre.

dence of conventional carcinoma, adenocarcinoma or squamous cell carcinoma associated with sarcoma of the conventional type. Immunohistochemistry on the resection specimen revealed focal reactivity for epithelial membrane antigen (EMA) and Dako Monoclonal Mouse Anti-Human Cytokeratin antibody MNF 116. There were no reactions to CD99, Desmin, S100 and fluorescence in situ hybridization (FISH) EWSR1 (22q12). No metastases were found in the lymph nodes. There were however some satellite nodules in the same lobe and the patient was staged pT3N0M0 according to the 7th TNM classification. Based on the patient’s age, complete resection of the lesion and the lack of evidence supporting adjuvant therapy, he received no further treatment. One year later, the patient was diagnosed with a locoregional recurrence and bone and liver metastases. Chemotherapy with Sorafenib was initiated. The patient died of an intestinal perforation 1 week later. 3. Discussion Pulmonary blastoma comprises only 0.25–0.5% of malignant lung neoplasms. This tumor was first recognized by Barrett and Barnard in 1945 and was termed embryoma of the lung due to its histologic similarity to fetal lung tissue [1,2]. In 1961, Spencer recategorized this neoplasm as pulmonary blastoma [3]. Pulmonary blastoma is currently subdivided in three categories: welldifferentiated fetal adenocarcinoma (WDFA), pleuropulmonary blastoma (PPB) and classic biphasic pulmonary blastoma (CBPB). WDFA was identified by Kradin et al. [4] in 1982 and consists only of

Fig. 2. Biphasic aspect of the tumor with a large undifferentiated stroma and branching epithelial tubuli (Hematoxylin and Eosin Stain).

an epithelial component. According to the 2004 WHO classification, WDFA is categorized as a variant of adenocarcinoma of the lung [5]. Recently, a new multidisciplinary classification of adenocarcinoma was published, in which fetal adenocarcinoma remains classified as a variant of adenocarcinoma [6]. PPB was identified by Manivel et al. [7] in 1988 and consists only of mesenchymal cells. This neoplasm occurs exclusively in children less than 15 years of age, with a median age of 3 years and one-fourth are hereditary. Unlike CBPB and WDFA, PPB was observed not only in the lung but also in extrapulmonary tissues as the pleura and the mediastinum. It is currently recognized as a distinct clinico-pathological entity different from the ordinary pulmonary blastoma of adulthood. CBPB is the only biphasic subgroup, characterized by a histological heterogeneity of mixed epithelial and mesenchymal malignancies. In the most recent WHO classification, CPBP is now among carcinomas with pleomorphic, sarcomatoid or sarcomatous elements. Much of the world literature is derived from isolated case reports or the experience of multiple centers over several decades. Koss et al. collected 53 cases of pulmonary blastoma from the files of the Armed Forces Institute of Pathology for the period from 1948 to 1988 [8]. Larsen and Sorensen collected 202 cases by a Medlinesearch between 1962 and 1995 [9]. In the current article, we give an overview of the cases obtained by a Medline-search between 1995 and today (Table 1). We excluded PPB, combined germ cell tumors and cases with unreported survival times. The majority of patients with CBPB and WDFA are adults with an average age of 43 years [8]. Larsen and Sorensen report a bimodal age distribution, one peak in the first and one in the seventh decade of life [9]. Koss et al. report an unimodal age peak in the fourth decade [8]. In our review, the average age was 39 years for both WDFA and CPBP. Although the small number of cases prevents defining an exact causative agent, 82% of patients with CPBP and WDFA have a history of tobacco use [8]. Furthermore adducts of benzpyrene (a product in tobacco smoke) have been detected in pulmonary blastomas [10]. A p53 gene mutation with or without p53 protein overproduction has been linked to both CBPB and WDFA whereas PPB seems to be associated with a chromosome 2 trisomy [11–13]. Cystic pulmonary disease has been related to PPB and PB in children, and so has an inherited germ-line mutation causing cystic nephroma [9]. Some groups report a male predominance in WDFA and CBPB [4,9,14], whereas others have not [8,15,16]. In our review, 29 cases were men and 30 cases were woman. The CBPB-subtype had a gender ratio that favored men by 1.5:1, whereas the WDFA-subtype had a gender ratio that favors woman by 3:1. A theory relating to the WDFA-subtype argues that the female predominance might be due to female sex hormones influencing the differentiation and malignant potential of fetal lung development, even though receptors for sex hormones have not been demonstrated [9]. About 40% of all patients are asymptomatic. CBPB frequently appear as large tumors: Koss et al.’s 24 cases average 10.1 cm in their largest diameter. Not surprisingly, the majority of these patients are symptomatic. WDFA is usually a smaller tumor (<5 cm) and more likely to be asymptomatic [8]. In our review, the average diameter is 9.1 cm for the CBPB-subtype and 5.7 cm for the WDFAsubtype. Cough, chest pain, haemoptysis, dyspnea and respiratory distress are common presenting features, but fever, anorexia, weight loss, fatigue, multiple chest infections, spontaneous pneumothoraces, pleural effusions and neurological symptoms have also been reported. Abnormalities in laboratory tests are nonspecific. No serum tumor marker is specific for PB [17]. Pulmonary blastoma usually presents as a well-defined lesion on the chest radiography, which may be large enough to completely opacify the hemithorax and cause mediastinal shift. The majority of the lesions are large, solitary, peripheral nodules [18]. On CT, pulmonary blastoma is seen as a mixed solid and cystic lesion

Table 1 Overview of cases of pulmonary blastoma between 1995–2010. Age (yrs)

Sex

Size (cm)

Lobe

Stage

Surgery

1 2 3 4 5 6 7 8 9 10 11 12 13

WDFA CBPB CBPB CBPB PB CBPB CBPB CBPB CBPB CBPB CBPB CBPB CBPB

33 37 57 54 21 59 27 30 22 53 72 77 49

F F F M M M M F M M M M M

9 7 1.5 21 ? 3.5 10 ? ? 17 8.5 10 ?

RLL LLL LLL LUL RLL LLL LLL RUL L?? LLL RLL LUL L??

T2N1M0 T2,3?N0M0 T1N0M0 T4?N2?M0 T4N0M0 T2N0M0 T2?N0 T3N0M0 ?M0 T2?N0M0 T2?N0M0 T4N0M0 minT2N0M0

pneu lob+sleeve seg pneu+peri pneu lob lob lob pneu+peri lob lob lob

14

CBPB

?

M

?

?

?

lob

15 16

CBPB CBPB

16 17

M M

? 16

bilat RUL

T4NxM1 T3N0M0

lob

17 18

CBPB CBPB

67 23

M M

13 8

? ?

T4NxMx T2NxM1

19 20 21

WDFA WDFA CBPB

44 57 24

M F F

9 4 15

? RUL LUL

T4N0M0 T2N0M0 T4N0M0

pneu lob lob

22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43

WDFA PB PB PB PB PB CBPB CBPB CBPB CBPB CBPB CBPB WDFA CBPB CBPB CBPB CBPB CBPB CBPB CBPB CBPB CBPB

27 32 39 46 34 33 ? ? ? ? 19 44 37 56 29 69 21 41 73 61 28 27

F F F F M F ? ? ? ? F M F M F M F F F M M F

9 5 12 6 13 12 ? ? ? ? 12 7 2 3 15 3.5

T4N0M0 T3N2M0 T3N1M0 T3N2M0 T3N2M0 T3N2M0 T?N1M0 T?N0M0 T?N0M0 T?N0M0 T2N1M0 T2N0M0 T1N0M0 T1N2M0 T4N0M0 T2N0M0 T4N2M1 T4N2M1 T3N0M0 T2N0M0 T1N0M0 T2N1M0

pneu lob pneu lob pneua lob 1 seg, 3 lob

3.5 3.6 3 6

? LUL L?? LUL L?? RUL R?L R?L R?L R?L LLL RUL RLL LUL LUL, LLL RUL R?? L?? LLL RLL LLL RUL

44 45 46 47 48

CBPB CBPB CBPB PB PB

27 54 40 85 40

M M F F F

17 6.5 4.6 8 7

RML RLL RUL RLL LUL

T2N1M0 T2N1M0 T2N2M0 T2N0M0 T2N0M0

pneu lob lob lob lob

CT

(3) Pt, VP-16 (3) Cyclo, Doxo, Pt

RT

Outcome (months)

Refs.

Alive wr 12 Alive wr 6 Alive wr 36 Alive wr 84 DOD 16 DOD 14 Alive wr 8 Dead unrel 23 Alive wr 36 DOD 12 DOD 6 Alive wr 12 Alive with disease 12

[36] [37] [38] [31] [39] [40] [30] [23] [41] [42]

DOD 12

[44]

DOD 12 DOD 41

[45] [19]

(1) 24Gy

DOD 3 DOD 8

[27]

(3) 50 Gy, (4) 42.5 Gy

Alive wr 55 Alive wr 52 Alive wr 35

(3) 60 Gy (4) 60 Gy, +

(3) Pt, Vds (3) x (4) Pt, VP-16

(1) Cyclo, Doxo, VP-16 (4) Pt, VP-16 (4) Pt and VP-16, If and VP-16 1st line; Vin 2d line (1) Pt, VP-16 (3) Epi, If (4) Gem, Carbo, stop-flow(Carbo, Mel), 2nd line Vin

(4) 50 Gy (3) 50 Gy (1) 20 Gy, (4) 20Gy

(1) Vcr, Act, Cyclo, Pt, Doxo

lob lob lob lob+sleeve pneub lob decort part lob lobc lob wedge, lob lob

(2) Vcr, Act, If, Doxo, VP-16, Carbo (2) MM-C, If, Pt (3) x (3) x

(3) Pt, VP-16, Uro, If (3) x

(3) x (3) x

(3) 64 Gy

(3) x (3) x (3) x

(4) Vcr, Cyclo, If, VP-16 (4) 40 Gy (4) Vcr, Cyclo (3) x

(3) x

Alive wr 29 DOD 7 DOD 17 DOD 6 DOD 30 Alive wr 33 DOD 22 Dead unrel 6 Alive wr 70 Alive wr 158 Alive wr 6 Alive wr 132 Alive wr 27 DOD 15 DOD 15 DOD 45 DOD 6 DOD 4 Alive wr 30 Dead unrel 112 Alive wr 198 DOD 17 DOD 9 DOD 10 Alive wr 14 Dead unrel 80 Alive wr 108

[43] [10]

[16]

[46]

[47]

[48] [18] [49] [20]

[50] [26]

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Type

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Pat

(4) 40 Gy (3) Carbo, Pac (3) x (4) If, Doxo, Len 2nd relaps: Carbo, Vcr/Cyclo, Act/Doc, Gem

pneu, pneumonectomy; peri, pericardiectomy; lob, lobectomy; seg, segmentectomy; Pt, cisplatin; Gem, gemcitabine, Doc, Docetaxel; Act, actinomycin-D; Len, lenograstim; Mel, Melphalan; Vcr, vincristine; Uro, uromitexan; Sor, sorafenib; Cyclo, cyclophosphamide; MM-C, mitomycin-C; If, ifosfamide; Vin, vinorelbine; Bev, bevacizumab; Carbo, carboplatin; Epi, epirubicine; Pac, paclitaxel; Doxo, doxorubicin; Vds, vindesine; VP-16, etoposide; Pem, pemetrexed; wr, without recurrence; DOD, Death of disease; unrel, unrelated; 1, sole therapy; 2, neoadjuvant; 3, adjuvant; 4, for recurrence; decort, decortication. a With diaphragm. b With pleural resection. c With bronchoplasty. d Intrapericardial pneu.

[53] [54] [55] [22] [56] [57] Alive wr 3 Alive wr 36 DOD 7 Alive wr 30 DOD 18 DOD 29 (3) 60 Gy (3) Carbo, VP-16, If

lob pneud lob pneu pneu pneu+peri T2N0M0 T4N0M0 T3N0M0 T3N0M0 T2N1M0 T3N0M0 RUL LUL RUL RUL RUL R?? 4 15 8 1 6 12 25 47 75 39 61 22 WDFA CBPB CBPB WDFA CBPB CBPB 58 59 60 61 62 63

F F M M F F

(4) x (3) Carbo, Gem (4) Pem, Bev/Sor

(4) x

Outcome (months) RT CT

Dead unrel 29 Alive wr 84 Dead unrel 24 Alive wr 29 Alive wr 25 Alive wr 36 DOD 24 Alive wr 36 Alive recurrence? 36 lob lob wedge lob lob lob+sleeve pneu lob lob

Surgery Stage

T2N0M0 T2N0M0 T2N0M0 T2N0M0 T2N0M0 T2N0M0 minT2N0M0 T2N0M0 T4N?M0 RUL RLL LLL LUL LUL RUL LUL RLL RUL

Lobe Size (cm)

5 6 3.2 4 4 7.9 10 7 9.2 M F M F F F M M F

Sex

66 44 81 48 39 52 51 73 37 PB PB PB PB PB WDFA CBPB CBPB CBPB 49 50 51 52 53 54 55 56 57

Age (yrs) Type Pat

Table 1 (Continued)

[51] [28] [52] [29]

S. Van Loo et al. / Lung Cancer 73 (2011) 127–132

Refs.

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with variable contrast enhancement and a necrotic centre. Pleural effusion may be present and is more likely to occur in CBPB than in WDFA. The tumor is usually limited to one lung, with all pulmonary lobes equally affected [16]. Only 25% exhibits endobronchial growth [20]. In our series, we report only one case of bilateral disease. 27 cases were left-sided tumors and 31 cases were located in the right lung. We did however find an upper lobe predominance, with 27 tumors located in the upper lobes, while 19 tumors were located in the lower lobes and 1 in the middle lobe. Other authors have previously reported an upper lobe predominance [19,21,22]. Preoperative diagnosis by bronchoscopy, needle biopsy or other methods is difficult due to the pleomorphic pattern characteristic for PB. Although establishing a preoperative diagnosis of pulmonary blastoma by examining histologic or cytologic specimen is difficult, the possibility of pulmonary blastoma should be considered when a two-cell pattern consisting of both epithelial and mesenchymal components is observed [23]. At bronchoscopy, some of the tumors have an associated finger-like or polypoid endobronchial component, though the tumor itself does not originate from the bronchus. Microscopically, the tumor resembles first trimester fetal lung. CBPB is a biphasic neoplasm, with a mixture of malignant epithelial and stromal cells. The epithelial component consists of tubular adenocarcinoma with glycogenated cytoplasm. The stroma consists of loose undifferentiated mesenchyme and may have variable degrees of nuclear atypia. The primitive stroma may contain foci of osteosarcoma, chondrosarcoma, or rhabdomyosarcoma. The glandular cells are strongly reactive for keratin, carcinoembryonic antigen and milk fat globulin and often chromogranin. Vimentin, actin and less desmin and myoglobin are mesenchymal markers [10]. The mesenchymal element sometimes shows differentiation into fibrocystic tissue, smooth muscle, cartilage, bone, or neuroendocrine cells [8,9]. Although often seen in WDFA, morules composed of rounded polygonal cells with ample eosinophilic finely granular cytoplasm are uncommon in CBPB. WDFA is composed of neoplastic glands with glycogen-rich, nonciliated tubules accompanied by mesenchymal tissue histologically benign in appearance. WDFA is less likely to have nuclear pleomorphism or frequent mitosis [8]. The histogenesis of CBPB is still under discussion. Some authors proposed an endodermal or mesenchymal origin, while others suggested that both components are derived from a single pluripotential cell. Evidence for an origin of both cell populations by a single clone came from Bodner and Koss who demonstrated mutations in the p53 gene and protein overexpression in the epithelial as well as the stromal component [11]. Hansen et al. reported expression of CD117 in both components [24]. Yousem et al. observed simultaneous expression of cytokeratin and vimentin in the blastomatous component, which provides further support for a single origin [25]. Recent studies have demonstrated beta-catenin gene mutations in CBPB and (more frequently) WDFA with aberrant nuclear/cytoplasmic localization of beta-catenin. The mutation is associated with a common histological feature, namely morule formation. The presence of this genetic alteration found in both WDFA and CBPB implies a histogenetic linkage between these tumors. By contrast, most conventional lung carcinomas show membranous localisation of beta-catenin with no mutations in the gene [12,13]. Surgery is the treatment of choice for localized disease. Koss et al. reported a mean survival of 33 months in 66 resected cases compared to 2 months in 17 patients with unresected disease [8]. Larsen et al. reviewed 108 resected cases of all three subtypes. The median survival for lobectomies or minor resections was 26 months and for pneumonectomies the survival was 9 months [9]. A study of 5 patients with CBPB by Liman et al. between 1987 and 2000 demonstrated long-term survival obtained by radical surgery in

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patients who have small size tumor (<5 cm) without nodal involvement [20]. Another study of 7 patients between 1993 and 2004 by Adluri et al. showed similar long-term survival by radical surgery in stage T2N0M0 [26]. Local recurrence has been treated successfully with surgery in a few cases [8]. Removal of distant metastasis also seems to prolong survival [27–29]. Radiation therapy given as a single therapy has induced an objective response in a few case reports [9,10]. However, the majority of the literature on the role of radiotherapy involves PPB and demonstrates no objective response. In most centers, radiotherapy is used to treat irresectable cases that do not respond to other forms of treatment. In a few reports local control and palliation of metastasis was achieved by radiotherapy combined with chemotherapy [10]. Radiation therapy has commonly been used as adjuvant therapy after resection of brain metastasis [27,28]. Larsen and Sorensen reported 26% overall response rate to firstline chemotherapy (without concurrent radiotherapy) in evaluable patients, while no objective response was observed in 18 patients who received chemotherapy as a second-line treatment. An objective response was achieved by a combination of multiple drugs but not by any single agent. They advised to use regimens containing alkylating agents, antibiotics or antimitotic agents [9]. However, the optimal combination of chemotherapeutics remains to be determined. The mixed histology of biphasic blastoma containing both carcinomatous and sarcomatous elements led to the combination chemotherapy of alternating cycles of agents, potentially effective against both histologies [14]. Combination chemotherapy of agents as cyclophosphamide, vincristine, doxorubicin, and dactinomycin has been used for many patients because of its effectiveness in the treatment of nephroblastoma and rhabdomyosarcoma, which are histogenetically related to pulmonary blastoma. Medbery et al. published the first review on chemotherapy in 1984 and report an objective response with this four-drug combination [14]. Cisplatin is frequently used because of its efficacy in the treatment of other primitive tumors including Wilms’ tumor and most germ cell tumors and because of its common effect on different types of lung neoplasms including small cell and non-small cell lung cancers [30]. Based on a review of all cases published between 1982 and 1994, Cutler et al. have recommended adjuvant radiotherapy and chemotherapy with cisplatin and etoposide (VP-16) as an effective regimen after surgery. Furthermore, they stated that cyclophosphamide and doxorubicin have been shown to be inactive against pulmonary blastoma [31]. However, in a patient with a non-metastatic tumor, an 11-year disease-free survival was reported with six cycles of cyclophosphamide, doxorubicin, and cisplatinum in addition to radiotherapy after resection [32]. Nissen et al. obtained complete remission of a recurrence of PB after pneumonectomy with a regimen containing CCNU, vincristine, VP-16 and cyclophosphamide [33]. Using an adjuvant protocol similar to the one used in the treatment of germ cell tumors (cisplatin, VP-16, uromitexan, ifosfamide and 64 Gy of mediastinal radiotherapy), a Swiss group reported a 33-month survival in a patient with stage pT3N2M0 [16]. The available literature on neoadjuvant chemotherapy preceding surgical resection is scarce. Büchel et al. reported an 8-month disease-free survival with neoadjuvant chemotherapy (etoposide and cyclophosphamide) combined with adjuvant chemotherapy (carboplatin and etoposide) [34]. Zaidi et al. reported a substantial response that led to successful resection and long-term survival in 2 patients. The regimens contained either cisplatin or carboplatin and ifosfamide. They concluded that surgical resection should be contemplated in all patients, with neoadjuvant chemotherapy used in an attempt to downstage advanced tumors before resection [27]. A recent case by Zagar et al. describes a large, irresectable recurrence of classic biphasic pulmonary blastoma that was suc-

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cessfully downstaged by neoadjuvant radiotherapy combined with chemotherapy [35]. Pulmonary blastoma has a high proliferative activity in both mesenchymal and epithelial components with a higher vessel density at the periphery of the tumor compared with the central part. Thus, angiogenesis may be essential for pulmonary blastoma tumor growth. Sorafenib, an angiogenesis inhibitor, was used with good response in a patient with renal metastasis of a pulmonary blastoma [29]. Our patient died of intestinal perforation a few days after the first dose of sorafenib was administered, so no conclusions concerning the efficacy of the drug can be made. The prognosis of pulmonary blastoma is poor. Although there are individual reports of long-term tumor-free survival, two thirds of patients die within 2 years of diagnosis, 16% survive 5 years and only 8% survive 10 years [8]. WDFA appears to have a better prognosis with a median survival of almost 3 years [17] and a recurrence rate of 29%. CBPB has a recurrence rate of 43% and a propensity for metastasizing to the brain, mediastinum, pleura, diaphragm, liver, heart, and soft tissues of the extremities. Curiously, metastases of CBPB – be it lymphatic or in another organ – do not necessarily reproduce the biphasic primary tumor architecture: patients whose metastases were examined showed evenly distributed monotype and mixed histologies [16]. Recurrence of disease seems to occur during the first 12 months after diagnosis or not at all [9]. Adverse prognostic factors for patients with biphasic tumors are tumor recurrence, metastasis at initial presentation and gross size of the tumor (>5 cm). For patients with WDFA, the presence of thoracic adenopathy, metastasis at initial presentation and tumor recurrence are the factors most highly correlated with poor prognosis [8].

4. Conclusion A classic biphasic pulmonary blastoma is part of a rare group of malignant lung neoplasms with a poor prognosis. Because of the rapid progression of the tumor, an initial aggressive treatment that includes surgery and, wherever possible, postoperative chemotherapy and radiotherapy could be useful to prolong survival in patients with this rare lung neoplasm. Chemotherapy is recommended in nonsurgical cases to attempt downstaging, in cases with involvement of surgical borders and cases with adverse prognostic factors (biphasic type, tumor recurrence, metastasis at initial presentation, gross size of the tumor (>5 cm) and lymph node involvement). Radiotherapy is advised to sites with residual disease or for palliation of metastatic disease. Radiotherapy can also be used to attempt downstaging. The recurrence rate is high, especially in CBPB, therefore a careful follow-up is required, especially during the first postoperative year. Furthermore, it is important to unify individual experiences from different institutions in a central registry in order to improve treatment and prognosis. With this review we hope to contribute to this by giving an overview of all cases of pulmonary blastoma of the last 15 years, the stage, treatment and outcome.

Conflict of interest statement None of the authors have any conflict of interest.

Acknowledgements We thank Dr. Nicolas Penel, Dr. Alfonso Baldi and Dr. Gaetano Caramori for their help in collecting the data.

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