Primary Lung Cancer in Lung Transplant Recipients Anne B. M. Olland, MD, MS, Pierre-Emmanuel Falcoz, MD, PhD, Nicola Santelmo, MD, Romain Kessler, MD, PhD, and Gilbert Massard, MD, PhD ˇ

Groupe de Transplantation Pulmonaire, Hopitaux Universitaires de Strasbourg, Strasbourg; and EA7293, Stress Vasculaire et Tissulaire en Transplantation, Universit
e de Strasbourg, Facult
e de Pharmacie, Illkirch, France

Risk factors for lung cancer in lung transplant recipients are a history of smoking and immunosuppression, to which adds increasing use of lungs from donors with a smoking history. The three typical presentations are incidental diagnosis on the explanted lung, concerning less than 2%; lung cancer developing on the lung graft, accounting for less than 1%; and incidence of lung cancer on the native lung, estimated at 9%. Treatment along

available guidelines may be hampered by decreased lung function owing to chronic rejection or adverse effects of immunosuppression. Prognosis is comparable to a general population in resected stage I cancer and is less favorable in advanced stages.

A

Recipient Risk Factors

fter 3 decades of clinical experience, lung transplantation (LTx) has evolved from a high-risk procedure with an uncertain outcome toward a validated radical treatment for end-stage respiratory disease. In 2009 more than 3,200 transplantations were performed worldwide [1]. Immediate and long-term survival has gradually improved since 1988 [1]. Malignancies are a common problem after LTx: at least one malignancy is diagnosed in 13% of 5-year survivors and in 28% of 10year survivors [1]. Solid tumors are the third cause of death among recipients surviving more than 1 year [2]. As consequence of the gradually increasing posttransplant survival, the prevalence of malignancies is expected to increase. Five-year survival was estimated at 53% during the most recent period reported by the International Society of Heart and Lung Transplantation Registry [1], and may exceed 60% in some selected centers of excellence [3, 4]. As a result, LTx recipients now present with the strongest standardized incidence ratio for lung cancer after solid organ transplantation [5]. Compared with the general population, patients who receive heart or lung allograft have a relative risk for bronchogenic carcinoma of 9.9 [6].

Risk Factors for Lung Cancer Related to LTx Recognized risk factors are environmental exposure of the recipient and the relatively stronger immunosuppression used in LTx recipients, to which is added chronic lung disease [7]. Increasing use of extended donor lungs, including those of smokers, leads to a potential additional risk.

Address correspondence to Dr Massard, Groupe de Transplantation Pulmonaire, Nouvel Hopital Civil, Hopitaux Universitaires de Strasbourg, 1 place de l’Hopital, 67000 Strasbourg, France; e-mail: gilbert.massard@ chru-strasbourg.fr. ˇ

ˇ

ˇ

Ó 2014 by The Society of Thoracic Surgeons Published by Elsevier Inc

(Ann Thorac Surg 2014;-:-–-) Ó 2014 by The Society of Thoracic Surgeons

In a general population, the risk for lung cancer increases with age: crossing the age of 60 years doubles the risk for lung cancer [8]. We should stress that 20% of LTxs performed since 2001 have been in recipients older than 59 years [1]. Further, mean age at the time of LTx has progressively increased to 50.8 years in 2009. Contemporary survival rates offer a decade of survival to 29% of recipients, who will cross the risk-threshold of 60 years [1]. Terminal respiratory illness qualifying for LTx and lung cancer share common occupational and environmental risk factors, of which smoking is the most frequent; in addition, exposure to asbestos or silica should also be mentioned. An independent risk is credited to interstitial lung diseases, such as idiopathic pulmonary fibrosis and systemic sclerosis, because of overlapping molecular pathogenic pathways [9]. Passive smoke exposure is a recognized risk factor [10, 11]. Genetic abnormalities of the epithelial growth factor receptor can lead to terminal respiratory unit type adenocarcinoma, even in nonsmokers, and is typically more frequent in Asian women [12]. Immunosuppression used for solid organ transplants generates a human immunodeficiency virus–infection like effect, doubling the risk for virus-induced malignancy [13]. In addition, immunosuppression may decrease the immune antitumoral response [14, 15]. Immunosuppressive drugs also act directly on carcinogenic pathways. Calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, may enhance tumor progression by inhibition of DNA repair [16], antiapoptotic effect in damaged cells [17, 18], and inhibition of cell adhesion favoring cell migration and metastatic spread [19, 20]. Azathioprine may induce squamous cell carcinoma of the skin [21, 22] and favors microsatellite DNA instability in myelodysplastic syndromes [23]. However, newer immunosuppressive drugs, such as mycophenolate mofetil (MMF) and inhibitors of mammalian target of rapamycin (mTOR), demonstrate 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2014.04.014

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donor lung harvest is easy to evaluate, there are few and controversial data on the long-term risk of lung cancer after transplantation of marginal lungs.

Abbreviations and Acronyms BAC BLTx BOS CNIs COPD

= = = = =

DFI LTx MMF NM P-Y SLTx SqCC

= = = = = = =

bronchioloalveolar carcinoma bilateral lung transplantation bronchiolitis obliterans syndrome calcineurin inhibitors chronic obstructive pulmonary disease disease-free interval lung transplantation mycophenolate mofetil not mentioned pack-years single lung transplantation squamous cell carcinoma

Material and Methods

the ability to reduce tumor progression [24–26]. There is no evidence that steroids enhance tumor progression. Single LTx (SLTx) creates a situation of combined risks, when the remaining native lung formerly exposed to inhaled risk factors is subjected to the stress of immunosuppression.

Donor Risk Factors The increased use of marginal donor lungs includes lungs from smokers and those of advanced age. Data from the United Network for Organ Sharing registry show that use of lungs from donors aged older than 55 years has doubled from 2000 (5.8%) to 2009 (10.0%) [27]. From 2005 to 2011, 766 donors used for 5,900 bilateral LTx (BLTx; 13%) were heavy smokers (>20 pack years) [28]. Although the risk of incidental carcinoma at the time of

We reviewed Medline 1990 to September 2013 using the Ovid interface, limiting the search to articles published in English and using the following search words: “bronchogenic carcinoma.mp” and/or “lung cancer.mp” and “lung transplantation.mp” and/or “lung allograft.” We found 989 references from which we retrieved manually the relevant articles. We focused on three settings: (1) lung carcinoma in the explanted recipient lung, (2) lung carcinoma occurring in the native lung after SLTx, and (3) lung carcinoma occurring in a transplanted lung. Eventually, we found 30 articles dealing with lung cancer associated with LTx.

Results Clinically Occult Bronchogenic Carcinoma in the Explanted Recipient Lung We identified 11 referring references [29–39] (Tables 1, 2). We excluded transplantation for bronchioloalveolar carcinoma. Occult cancer was defined as small tumor foci (1) ignored by pretransplant imaging and discovered intraoperatively or (2) indeterminate nodules without any characteristics of malignancy. Incidental bronchogenic carcinoma of the explanted lung raises several questions regarding follow-up of patients listed for LTx: 1. Should patients listed for LTx be periodically screened for new parenchymal abnormalities?

Table 1. Reported Cases and Cases Series of Primary Lung Cancer Incidentally Found in the Explanted Lung of Recipients During the Lung Transplant Procedure Reference Svendsen [29]

Cases/No. of LTx (%)

Recipient Age at LTx (y)

2

57 58 55 52 64 NM

Stagner [30] Arcasoy [31]

1/45 (2) 2/251 (0.8)

De Perrot [32]

5/852 (0.6)

De Perrot [33]

43/8000 (0.5)

Abrahams [34]

4/214 (2)

Ritchie [35] Delgado [36] Minai [37] Raviv [38]

1 1/129 (0.8) 4/520 (0.8) 2/211 (0.9)

Strollo [39]

17/759 (2.2)

COPD ¼ chronic obstructive pulmonary disease;

Smoking History

LTx Indication

COPD COPD Fibrosis COPD COPD Emphysema (n ¼ 2) Fibrosis (n ¼ 3) Median age 56 Yes (n ¼ 35) Emphysema (n ¼ 26) Fibrosis (n ¼ 11) Mean age 57 Yes (n ¼ 2) Emphysema (n ¼ 3) Fibrosis (n ¼ 1) 41 NM Fibrosis Excluded from the study, no other information available Excluded from the study, no other information available 68 Yes Primary pulmonary hypertension NM No Fibrosis 61 Yes (n ¼ 17) Fibrosis (n ¼ 8) Emphysema (n ¼ 7) Fibrosis & emphysema (n ¼ 2) LTx ¼ lung transplant;

Yes Yes Yes Yes 100 P-Y Yes 84 P-Y NM

NM ¼ not mentioned in the article;

P-Y ¼ pack-years.

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Table 2. Outcome of Patients With Primary Lung Cancer in the Explanted Native Lung Reference

Histology

Stage

Svendsen [29]

Adenocarcinoma Adenocarcinoma Stagner [30] Adenocarcinoma Arcasoy [31] Adenocarcinoma Adenocarcinoma De Perrot [32] BAC Adenocarcinoma Adenocarcinoma BAC Lymphangitic carcinomatosis

T1 N0 M0 T1 N0 M0 T2 N1 M0 T4 N0 M0 IA T1 N0 T1 Nx T2 Nx T4 N2 Diffuse, Tx Nx

De Perrot [33] Adenocarcinoma (n ¼ 15) SqCC (n ¼ 9) Multifocal BAC (n ¼ 7)

Stage I (n ¼ 22) Stage II (n ¼ 12) Stage III (n ¼ 2) Incidental multifocal BAC (n ¼ 7) Stage I in 3 patients Stage IV in 1 patient with ADK Multifocal

Abrahams [34] Adenocarcinoma (n ¼ 3) SqCC (n ¼ 1) Ritchie [35] Raviv [38] Strollo [39]

Adenocarcinoma, TT F1 negative SqCC Adenocarcinoma Adenocarcinoma (n ¼ 9) SqCC (n ¼ 5) Sarcomatoid-like (n ¼ 1) Lymphoepithelial-like (n ¼ 1) Atypical carcinoid (n ¼ 1)

BAC ¼ bronchioloalveolar carcinoma;

Stage Stage Stage Stage Stage

Outcome and Survival Alive 34 months after transplantation Alive Died 10 months after transplantation from recurrence Died 20 months after transplantation from recurrence Died 8 months after transplantation, brain and bone metastases Alive 12 months after transplantation Died 5 and 6 months respectively after transplantation from recurrence Died 35 months after transplantation from recurrence Died 10 months after transplantation from BOS, no evidence of cancer recurrence Stage I: 5-year survival, 51% Stage II and III: significantly lower survival Incidental multifocal BAC: significantly lower survival

1 patient with stage I SqCC alive 6 years after transplantation 5-year survival: 25% in patients with carcinoma of the explanted lung; 40.6% in patients without malignancy Alive at 3 years with standard immunosuppression

I II I (n ¼ 8) II (n ¼ 5) III & IV (n ¼ 4)

Alive at 7 years with standard immunosuppression Died postoperative complication 3 patients with malignancy recurrence in the allograft Died within 1 year posttransplant

BOS ¼ bronchiolitis obliterans syndrome;

2. What are the indications for adjuvant treatment and what follow-up schedule should be used after LTx? 3. Should immunosuppression be modulated? 4. Does the natural history of lung cancer affect the outcome of LTx?

Prevalence and Risk Factors The prevalence of incidental cancer in the explanted lung ranged from 0.8% to 2.2% [30, 33, 36, 37, 39]. Adenocarcinoma was the most frequent histology (43%). Data on smoking were not reported for all patients, whereas emphysema and chronic obstructive pulmonary disease (COPD) were the most common indications (54%). Although lung cancer risk significantly increases above 60 years in a general population, mean age at diagnosis of lung cancer in LTx recipients was slightly younger, averaging 56 years. As such, age was a less potent risk factor compared with chronic lung disease and smoking history.

SqCC ¼ squamous cell carcinoma.

neither routine lung cancer screening nor positron emission tomography seemed practical or cost-effective to help in detecting malignancies during the LTx recipient’s preoperative work-up and waiting time [39]. Patients awaiting LTx are too ill to undergo monitoring of every indeterminate nodule for 2 years’ stability, and positron emission tomography has a substantial rate of false-positive or false-negative results [39]. If a suspect nodule were discovered in an actively listed patient, most teams would keep the patient on waiting list, provided that a complete workup ruled out advanced tumor stage [29, 32]. Some authors would mandate mediastinoscopy to exclude N2 disease. Transplantation in such patients is paradoxical, because a medical history of cancer usually contraindicates LTx. Transplantation can only be justified in stage I, where explantation of the recipient’s lung achieves a complete and curative resection.

Strategy for Lung Cancer Evidenced at Explantation Strategy for Lung Cancer Detected Before LTx Incidental carcinoma in explanted lungs occurs at a low prevalence. Moreover, reviewing chest imaging of patients diagnosed with lung cancer identified some small consolidation initially interpreted as infection or scars [32, 33]. Only Strollo and colleagues [39] addressed the relevance of routine lung screening or use of positron emission tomography in LTx patients. In their practice,

Only 2 authors forwarded precise statements regarding treatment and follow-up. Adjuvant chemotherapy was given in 1 patient with a T2 N1 cancer. In another patient, close follow-up demonstrated consolidation in the remaining native lung, and pneumonectomy was performed with curative intention. Although pneumonectomy at the time of transplantation may be considered to be curative, several authors stress completing mediastinal

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Table 3. Cases and Series of Primary Lung Cancer in the Native Lung During Transplantation Follow-Up Reference

Cases/No. of LTx (%)

Smoking History

LTx Indication

Stagner [30] Spiekerkoetter [40] La Fianza [41] Choi [42] Schulman [43]

1/46 1/239 1/54 1/90 2/82

McAdams [44]

3/111 (2.7)

Arcasoy [31]

4/125 (3.2)

60 NM 47 NM 59 55 56 57 NM Mean age 60

Collins [45]

24/975 (2.5)

Mean age 58

Lee [46]

2/140 (1.4)

Dickson [47]

9/131 (6.9)

64 55 Mean age 57

5/200 (2.5) 1/66 (1.5) 11/286 (3.8)

NM NM Mean age 58

NM NM Yes, 30 P-Y or more

Parada [48] Raviv [38]

1/59 (1.7) 7/211 (3.3)

NM Mean age 55

NM Yes in all patients

Ploenes [49] Yserbyt [50]

1 9/101 (8.9)

60 Mean age 63

Espinosa [51]

8/336 (2.4)

NM

NM Yes in all patients, average 29 P-Y Yes in 77% of all patients

Roithmaier [6] Delgado [36] Minai [37]

(4) (0.4) (1.9) (1.1) (2.4)

Recipient Age (y)

COPD ¼ chronic obstructive pulmonary disease;

Yes NM No Yes NM NM

Yes, 30 P-Y or more Yes in 19 patients, mean consumption 59 P-Y NM Yes in 9 patients

LTx ¼ lung transplantation;

staging with mediastinoscopy, with the back thought of potential adjuvant therapy. Tapering immunosuppression during the initial posttransplant period is hardly possible. Immunosuppressive therapy was modified only in 1 patient by withdrawal of MMF [35].

Overall Prognosis The International Society of Heart and Lung Transplantation Registry reports an overall 5-year survival rate of 53% [1]. In comparison, 5-year survival rates of patients with cancer of the explanted lung range from 25% to 51%, depending on the pTNM stage [33, 34]. According to De Perrot and colleagues [33], survival was significantly better for stage I disease (51% at 5 years) compared with stages II and III (14%). Patients discovered with multifocal bronchioloalveolar carcinoma had a poor prognosis (23% at 5 years) [33]. Most patients with stage II or III carcinoma experienced recurrence and died within the first year after transplantation [33].

Bronchogenic Carcinoma Arising in the Native Lung After SLTx We found 18 references [6, 30, 31, 36–38, 40–51] mentioning lung cancer of the native lung after SLTx (Table 3). The mean delay between LTx and diagnosis of bronchogenic carcinoma was 4 to 119 months. A

NM ¼ not mentioned;

Emphysema NM Fibrosis Fibrosis Emphysema Emphysema Emphysema Fibrosis NM COPD (n ¼ 3) Fibrosis (n ¼ 1) Emphysema (n ¼ Fibrosis (n ¼ 6) COPD COPD Emphysema (n ¼ Fibrosis (n ¼ 1) Emphysema (n ¼ Fibrosis COPD (n ¼ 10) Fibrosis (n ¼ 1) NM Emphysema (n ¼ Fibrosis (n ¼ 5 Emphysema Emphysema (n ¼ Fibrosis (n ¼ 4) COPD (n ¼ 5) Fibrosis (n ¼ 3)

18)

8) 4)

2)

5)

P-Y ¼ pack-years.

retrospective review of chest imaging identified a preexisting nodule at the time of transplantation in 1 patient [31]. Diagnosis was made during routine transplant follow-up or due to symptoms. Two patients presented with rapidly expanding malignant pleural effusions [31]. No author described a specific follow-up strategy focused on the risk for malignant change of the native lung.

Prevalence and Risk Factors We calculated the prevalence of bronchogenic carcinoma of the native lung by pooling the different publications and noticed a steady increase over time, ranging from 1.5% [36] in the first reports to 6.9% [47] and 8.9% [51] in the more recent studies. In the UK (United Kingdom) Transplant Registry, the standardized incidence ratio for primary lung cancer was 5.9 in LTx recipients, 2.1 in heart, and 1.6 in liver, and most primary lung malignancies occurred in the native lung [5]. Our review found the age of transplant recipients at the time of cancer diagnosis was slightly younger than 60 years. In three studies, all patients presenting with primary lung cancer of the native lung were former smokers, including patients with fibrosis [31, 40, 47]. Nevertheless, SLTx appears to be an independent risk factor for lung cancer after LTx compared with BLTx [47]. Referring to Dickson and colleagues [47], smoking history

Reference

Histology

Stage

Stagner [30] Spiekerkoetter [40] La Fianza [41] Choi [42] Schulman [43]

SqCC (n ¼ 1) SqCC (n ¼ 1) Adenocarcinoma (n ¼ 1) SqCC (n ¼ 1) SqCC (n ¼ 1) Adenocarcinoma (n ¼ 1)

Stage I NM Stage IV Stage I/II NM

McAdams [44]

Adenocarcinoma (n ¼ 1) Other bronchogenic carcinoma (n ¼ 2)

Stage I (n ¼ 2)

Arcasoy [31]

Adenocarcinoma (n ¼ 3) SqCC (n ¼ 1)

Collins [45]

SqCC (n ¼ 8) Adenocarcinoma (n ¼ 7) Other bronchogenic carcinoma (n ¼ 9)

Stage IA (n ¼ 7) Stage IB (n ¼ 2) Stage III or IV (n ¼ 7) Advanced disease without staging in 7 patients

Lee [46]

Bronchogenic carcinoma (n ¼ 2) SqCC (n ¼ 6) Adenocarcinoma (n ¼ 2) Other bronchogenic carcinoma (n ¼ 1)

Stage Stage Stage Stage

Dickson [47]

Stage IV Stage IA Stage IA Twice stage IIIB

II IIIB IA (n ¼ 5) IIB (n ¼ 1)

Roithmaier [6]

Delgado [36] Minai [37]

Other bronchogenic carcinoma (n ¼ 1) Small cell carcinoma (n ¼ 1) Other bronchogenic carcinoma (n ¼ 1) SqCC (n ¼ 3) Adenocarcinoma (n ¼ 3) Other bronchogenic carcinoma (n ¼ 3) Small cell carcinoma (n ¼ 2)

Surgical resection Surgical resection Refusal of chemotherapy Surgical resection Surgical resection (n ¼ 1) Chemotherapy and radiotherapy Mediastinoscopy and surgical resection Palliative treatment Surgical resection Pleurodesis Chemotherapy and radiotherapy in 1, pleurodesis in the other Surgical resection (n ¼ 9) Surgical resection and chemotherapy (n ¼ 2) No treatment in 8 patients Lost to follow-up (n ¼ 2) Radiotherapy (n ¼ 2) Chemotherapy (n ¼1) Palliative treatment Surgical resection possible in 5 patients

Advanced-stage disease in 4 patients: chemotherapy and radiotherapy possible in 2 patients Palliative radiotherapy in 1 patient No treatment in 1 patient

Advanced stages

Outcome and Survival Alive without recurrence Alive without recurrence Died 6 months after cancer diagnosis Alive with recurrence Alive without recurrence Died 18 months of recurrence Alive 6 and 12 months after surgical resection for cancer Died 6 months after cancer diagnosis Alive 1,021 days after surgical resection All other patients died of cancer

8 patients alive at the end of study 5 patients with disease-free interval >1 year 15 patients died (65%) Time from diagnosis to death: 3 days to 21 months; mean, 7 months Died 3 patients alive after stage IA (n ¼ 2) and stage IIA: surgical resection in 1, chemotherapy and radiotherapy in 2 From surgical resection: 3 of 5 patients with recurrence after a mean delay of 44 months 6 of 9 died all related to progressive or metastatic lung cancer Survival from the time of cancer diagnosis: 50% at 1 year, 25% at 5 years Died during follow-up period

Alive 4 months after diagnosis NM

3 patients with surgical resection 5 patients not amenable to surgical resection because of metastases 4 patients not amenable to surgical resection because of poor lung function or pleural involvement

Two patients still alive 90 and 26 weeks after resection and radiotherapy, respectively All other patients died of cancer or complication related to the treatment of cancer

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Stage IIIA (n ¼ 1) Stage III (n ¼ 1) Stage IV (n ¼ 1)

Treatment for Cancer

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Table 4. Outcome of Patients With Bronchogenic Carcinoma in the Native Lung After Lung Transplantation

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1 patient alive 1 patient died Alive All patients died Surgical resection (n ¼ 2) Pleurodesis

Chemotherapy Radiotherapy Best supportive care Surgical resection in all patients

Stage I (n ¼ 3)

Stage IV (n ¼ 6)

Calculated survival from cancer diagnosis 49.3  6.3 months (range, 0-180)

Died after 1 year of recurrent disease Died of postoperative complication Alive Died Died Alive Surgical resection in 1 Surgical resection and re-LTx for BOS in one Surgical resection (large cell carcinoma) Surgical resection and chemotherapy (n ¼ 1) No treatment (n ¼ 2) Surgical resection

Choice of treatment for lung cancer of the native lung after SLTx is modulated by the patient’s performance status, lung function, and adverse effects of immunosuppressive therapy. Surgical resection with curative intent should be the standard for early-stage disease. However, lung function may be jeopardized by chronic allograft dysfunction. Although indications for chemotherapy and radiotherapy as main or adjuvant therapy follow usual guidelines, adverse effects of immunosuppressive therapy, such as poor renal function, leucopenia, or neurotoxicity, may challenge the feasibility of chemotherapy. Immunosuppressive therapy itself is a risk factor for developing malignancy, but we found no recommendation on management of immunosuppression referring to lung cancer. Some authors modified the immunosuppressive regimen: discontinuation of azathioprine and decrease or withdrawal of CNIs [30, 38]. We found no reference citing use of mTOR inhibitors for their specific antimalignancy properties applied to lung cancer. No author reported search for epithelial growth factor receptor mutation or use of target therapy.

Overall Prognosis Pooling 91 patients from different reports, 24 patients (26%) were alive and free of disease at the time of publication; of these, 20 had early-stage cancer (22%) and underwent curative resection (Table 4), 3 patients underwent radiotherapy alone or with chemotherapy, and no details were given for the remaining patient [36]. Fiftyseven percent of patients with an early stage amenable to curative resection survived. Patients with more advanced stage had lower survival rates than expected. From the time of cancer diagnosis, survival ranged from 25% to 33% at 1 year and fell to 17% at 2 years [31, 37]. In comparison, survival rates for recipients without lung cancer were 70% at 1 year and 65% at 2 years [31]. We found no reference comparing lung cancer in those who did and did not receive a transplant.

Adenocarcinoma (n ¼ 3) SqCC (n ¼ 3) Large cell carcinoma (n ¼ 2) Espinosa [51]

Bronchogenic Carcinoma Developing in the Transplanted Lung SqCC ¼ squamous cell carcinoma.

Stage II

Other bronchogenic carcinoma Adenocarcinoma (n ¼ 3) Large Cell carcinoma (n ¼ 3) SqCC (n ¼ 1) Other bronchogenic carcinoma (n ¼ 2) Ploenes [49]

Yserbyt [50]

Stage IV (n ¼ 4) Adenocarcinoma (n ¼ 1) Other bronchogenic carcinoma (n ¼ 3)

SqCC (n ¼ 2) Raviv [38]

Therapeutic Strategy

Stage I (n ¼ 3) Stage II (n ¼ 4) Stage IIIB (n ¼ 1)

Died 8 months after cancer diagnosis Chemotherapy

Advanced disease with pleural effusion Stage I (n ¼ 2) NM Parada [48]

Reference

Table 4. Continued

Histology

Stage

Treatment for Cancer

Outcome and Survival

(hazard risk, 1.38) or increasing age (hazard risk, 1.03) appeared to be less potent risk factors compared with the relative risk of SLTx vs BLTx (hazard risk, 4.31) [47].

We found 11 references [6, 37, 38, 50–57] reporting primary lung cancer developing in a transplanted lung, most often after BLTx (Tables 5, 6). Prevalence of bronchogenic carcinoma in lung grafts has been rather stable over time, ranging from 0.3% to 0.4%. Only Yserbyt and colleagues [50] reported a higher prevalence of 1%. The hypothesis that use of lungs from donors who smoked increases the risk of lung cancer was challenged by a recent report of the Temple group (Philadelphia) [28]. Overall survival and functional outcome of LTx was not modified by the use of heavy smoker donors (>20 pack-years). The authors remained cautious about the conclusions of their

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Table 5. Cases Presenting With Primary Lung Cancer in the Transplanted Lung First Author De Soyza [52] De Perrot [53] Beyer [54] Picard [55] Roithmaier [6] Minai [37] Von Boehmer [56] Raviv [38] Yserbyt [50]

Espinosa [51] De Boer [57]

No. of Cases and Prevalence (%)

Donor Age (y)

1 50 BLTx 1/396 (0.3) 60 LTx 1 BLTx 55 1 BLTx NM 1/227 (0.4) BLTx No other information on the case 1/234 (0.4) NM BLTx 1 BLTx 60 1 SLTx 60 4 BLTx/393 (1) NM

Donor Smoking History

Recipient Smoking History

LTx Indication

NM

25

No

Cystic fibrosis

No

57

No

Emphysema

45 P-Y NM

54 25

100 P-Y NM

COPD Cystic fibrosis

50 P-Y

55

100 P-Y

COPD

20 P-Y NM Yes in all patients, average 29P-Y

Fibrosis Fibrosis Emphysema (n ¼ 3) Giant cell interstitial pneumonia (n ¼ 1)

No

Cystic fibrosis

No NM NM

61 NM 59

1 BLTx/336 LTx (0.3) No other precise information on the case 1 BLTx 56 No

BLTx ¼ bilateral lung transplantation; pack years.

Recipient Age (y)

17

COPD ¼ chronic obstructive pulmonary disease;

study because the incidence of lung malignancy had not been specifically recorded [28]. During the first few months after LTx appears a chimerism of lymphocytes, macrophages, and epithelial cells within the transplanted lungs [58–60]. A longitudinal study of transbronchial biopsy specimens showed presence of recipient epithelial cells in the graft after the first month [60]. This leads to the question of whether lung cancer occurring in lung grafts originates from donor’s or recipient’s cells. Three techniques allow investigating this question: genotyping of carcinomatous cells [52–54], detection of chromosome Y by fluorescence in situ hybridization when genders of donor and recipient differ [55], and human leukocyte antigen phenotype of tumors cells [56]. Among 13 reported cases, almost half originated from the donor’s tissues. Histology was documented in 8: 5 had adenocarcinoma and 3 had small cell lung cancer. The donor’s smoking history was not routinely registered, but reached 45 to 50 pack-years in 2 donors [37, 54]. Lung cancer originating from donor cells was reported in younger patients who received transplants for cystic fibrosis using lungs from donors aged from 50 to 60 years [52, 55]. In 3 patients, the immunosuppressive regimen was tapered once bronchogenic carcinoma was diagnosed [38, 55, 56]. Negative results were found in 1 patient tested for epithelial growth factor receptor mutation [57]. The limited number of reported cases opposes to any conclusion on prognosis. There were only 2 long-term survivors [54, 55]. One presented with operable earlystage cancer; the other had small cell carcinoma with ongoing chemotherapy at the time of publication. Two other patients presented with an early stage amenable to

LTx ¼ lung transplantation;

NM ¼ not mentioned;

P-Y ¼

curative surgical resection but died of neoplastic progression without a disease free-interval after the operation.

Peculiarities of Lung Cancer Treatment in LTx Recipients Prognosis of lung cancer in LTx recipients depends not only on stage but also on feasibility of active treatments, which should follow the currently validated guidelines. As such, surgical resection represents the optimal treatment for early-stage disease. In heart transplant recipients, surgical resection of early-stage lung cancer is associated with improved survival [6, 61]. In LTx recipients, all publications concluded prognosis was improved in patients fit to undergo lung resection. Neoadjuvant or adjuvant chemotherapy, or both, are discussed in case of node involvement; radiotherapy is added after R1 or R2 resection. Hence, particular attention should be addressed to mediastinal node staging in patients diagnosed with lung cancer on the explanted lung. Inoperable tumors are treated with chemotherapy or radiotherapy, or both. Targeted therapies may be used in the presence of appropriate mutations. Evaluation of fitness for surgical intervention is capital. Chronic allograft dysfunction may jeopardize lung function. The adverse effects of immunosuppression, such as diabetes, renal failure, hypertension, or cardiovascular comorbidity, may considerably increase operative risk and also interfere with the feasibility of chemotherapy. Modulation of immunosuppression remains controversial. Immunosuppression may decrease the efficacy of chemotherapy and increase its adverse effects [62–64]. Some experimental evidence shows that adjuvant

8

SLTx ¼ single lung transplant. DFI ¼disease-free interval; CNI ¼ calcineurin inhibitors; BLTx ¼ bilateral lung transplant;

De Boer [59]

Donor Adenocarcinoma

Yserbyt [50]

Raviv [38]

MMF ¼ mycophenolate mofetil;

Palliative

2 patients alive 15 and 17 months from cancer diagnosis Died Surgical resection (n ¼ 2) Chemotherapy (n ¼ 1) Combined modality (n ¼ 1)

Withdrawal of MMF or azathioprine in 7 patients, stop in CNI in 5 patients (overall information given on SLTx and BLTx patients) NM

Tapering or withdrawal of CNI Donor but no proof

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Adenocarcinoma Stage IV SqCC (n ¼ 2) Adenocarcinoma (n ¼ 1) Small cell carcinoma (n ¼ 1)

NM

Died no DFI

Died no DFI

Neoadjuvant chemotherapy followed with surgical resection No treatment Von Boehmer [56]

Adenocarcinoma supposed stage I Large cell carcinoma ypT4ypN2

Beyer [54] Picard [55]

Minai [37]

Donor acquired (HLA haplotype analysis)

Tapering in cyclosporine and MMF, increase in steroids

Died of recurrence Surgical resection NM

Alive Alive Surgical resection Chemotherapy still ongoing NM Discontinuation of MMF

Donor acquired (genotyping) Recipient acquired (FISH based on gender mismatch) NM

Died no DFI Died no DFI Chemotherapy Surgical resection Tapering in cyclosporine NM Donor acquired (genotyping) Donor acquired (genotyping)

Small cell carcinoma Stage IV Bronchoalveolar carcinoma T2 N0 Adenocarcinoma T1 N1 Small Cell Carcinoma De Soyza [52] De Perrot [53]

Origin of Neoplasm Histology First Author

Table 6. Origin and Outcome of Bronchogenic Carcinoma in the Transplanted Lung

Immunosuppression

Lung cancer Treatment

Outcome

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chemotherapy or radiotherapy is efficient in immunocompetent organisms only [62–64]. Immunosuppressive therapy itself is considered as a major risk factor for developing malignancy. Some authors modified the immunosuppressive regimen by discontinuation of azathioprine and decrease or withdrawal of CNIs [30, 38], without proven benefit. The switch to immunosuppressive drugs with antineoplastic properties, such as mTOR inhibitors, would be sound. Follow-up of kidney transplant recipients treated with sirolimus or everolimus, without CNIs, showed a lower incidence of malignancies [65]. Sathy and colleagues [66] reported failure of mTOR inhibitors in 2 LTx patients with allograft Kaposi sarcoma [66]. We found no reference citing use of mTOR inhibitors for lung cancer in LTx recipients. Antineoplastic use of mTOR inhibitors in LTx recipients needs further investigations. In conclusion, most LTx recipients share at least two potent factors for lung cancer: history of smoking and immunosuppression. The risk is highest at the site of the native lung after SLTx in a smoker. The best prevention is achieved by favoring BLTx rather than SLTx. Early diagnosis is capital for survival. Hence, periodic reevaluation should be planned for smokers on the waiting list; after transplantation, attention should be addressed to native lungs after SLTx and transplanted lungs originating from a donor with smoking history. Surgical resection is the mainstay of curative treatment. Currently available data do not allow for any recommendation regarding tapering of immunosuppression or use of mTOR inhibitors.

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