case report Wien Klin Wochenschr DOI 10.1007/s00508-015-0726-6

Lung cancer in pregnancy Kornelia Holzmann · Roland Kropfmüller · Herwig Schinko · Stephan Bogner · Franz Fellner · Wolfgang Arzt · Bernd Lamprecht

Received: 7 August 2014 / Accepted: 19 January 2015 © Springer-Verlag Wien 2015

Summary  In the 26th week of gestation, a 29-year-old pregnant office employee was referred to the pulmonary department of Linz General Hospital (AKH) under the suspicion of tuberculosis. She complained of a cough with intermittent hemoptysis and pain in the thoracic spine from which she had been suffering the past 9 weeks. A plain chest X-ray showed a dense infiltrate on the right side and multiple smaller shadows in both lungs. Laboratory testing revealed anemia, leukocytosis, and an increase of C-reactive protein. All tests for tuberculosis were negative. A bronchoscopy was performed and biopsies were taken from the right upper and middle lobe. The histopathological examination found cells of an adenocarcinoma. A magnetic resonance imaging (MRI) revealed a large tumor and surrounding atelectasis were seen in the right upper and middle lobe, as well as multiple intrapulmonary metastases in both lungs. In addition, not only metastases in the thoracic spine (level Th2/3) but also at other osseous locations and multiple cerebral metastases were detected. The patient received one cycle of chemotherapy consisting of docetaxel and carboplatin (AUC5) in the 27th week of gestation. Additional radio-

therapy was applied to the involved thoracic spine. Due to positive epidermal growth factor receptor mutation, therapy with gefitinib 250  mg/day was started 2 days after a Caesarean section (preceded by treatment for fetal lung maturation). A healthy girl was delivered in the 30th week of pregnancy. Staging with computed tomography (CT) after delivery revealed an unstable fracture of Th2 with compression of the spinal cord. Neurosurgery was performed, consisting of a ventral corporectomy of Th1–2 followed by an anterior and posterior osteosynthesis for stabilization. The patient was discharged without neurological deficits within 1 week. Subsequent treatment with gefitinib improved the performance status of the patient, and CT scans of the chest and an MRI of the brain showed the size of the tumor to be shrinking. Meanwhile, the infant developed appropriately for her age. After 14 months of the first diagnosis, the patient experienced neurological symptoms (aphasia, confusion) due to neoplastic meningeosis and cerebral venous sinus thrombosis together with local tumor progression in the lung. One course of chemotherapy, combining carboplatin/pemetrexed/bevacizumab, was given without clinical response. Despite best supportive care, the patient died 17 months after diagnosis in October 2013.

K. Holzmann () · R. Kropfmüller · H. Schinko · B. Lamprecht Department of Pulmonary Medicine, General Hospital Linz (AKH), Linz, Austria e-mail: [email protected]

Keywords  Pregnancy · Lung cancer · Gefitinib · Chemotherapy · Radiation therapy

S. Bogner Institute of Pathology, General Hospital Linz (AKH), Linz, Austria

Case report

F. Fellner Institute of Radiology, General Hospital Linz (AKH), Linz, Austria W. Arzt Institute of Prenatal Medicine, Linz, Austria

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In May 2012, a 29-year-old office worker was admitted to the gynecological and obstetrical department of a hospital in Linz due to a treatment-resistant cough with intermittent hemoptysis and attacks of dyspnoea from which she had been suffering from the past 9 weeks. The patient was in the 26th week of her first pregnancy, which up until then has followed an uneventful course. The young

Lung cancer in pregnancy  

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woman complained of pain in the upper thoracic spine. Apart from adynamia no further symptoms could be found especially no weight loss, no fever, and no night sweats. Hypothyroidism was substituted hormonally. For a total of 13 years, the patient had up until 2011, used oral contraception. For 3 years (until 2008), she had been an occasional smoker as well as being regularly exposed to second-hand smoke during and shortly after her apprenticeship as a bank clerk. There was no family history of cancer. The chest X-ray pa (see Fig. 1) showed a dense, twodimensional infiltration zone, which appeared in the right upper and middle lobe with additional focal opacities in the left lung. Hence, the patient was transferred to the department of pulmonary medicine at the General Hospital Linz under the tentative diagnosis of tuberculosis (TB).

Fig. 1  Chest X-ray posterior-anterior (pa) on admission

On admission, the patient was in a moderately good general condition with a blood pressure of 100/60 mmHg, a heart rate of 99/min, and a peripheral O2 saturation of 97 % in room air. On auscultation, a wheeze and hum on both sides could be heard, right more than left. Laboratory results showed: a normocytic, normochromic anemia with a hemoglobin level of 10.2 g/dl and an increase in inflammatory markers—leukocytes 13.12 G/l (12 % lymphocytes) and C-reactive protein 8.8  mg/dl. With regard to TB, the Quantiferon test was indeterminate, the Mendel–Mantoux test was negative, and the Ziehl–Neelsen stain, TB-PCR, and TB culture of bronchoalveolar lavage fluid were also negative. The bronchoscopy shows an edematous narrowing of the anterior segment of the right upper lobe and the middle lobe ostium. Six forceps-biopsies from the upper lobe and a bronchial lavage were carried out. Histological examination and additional immunohistochemistry confirm the diagnosis of an adenocarcinoma. ERCC1, thymidylate synthase, estrogen, and progesterone receptors were negative. The finding of the epidermal growth factor receptor (EGFR) status was positive in terms of exon 19 mutation. The tumor markers cancer antigen (CA) 19–9, carcinoembryonic antigen (CEA), Cyfra 21–1, CA 125, and CA 15–3 were all nonspecifically increased. However, for further staging adequate cross-sectional imaging was required. For the protection of the patient against an unnecessary burden of ionizing radiation during her pregnancy, it was decided that the primary staging should be carried out by means of a whole-body MR eliminating the use of a contrast agent. MRI of the chest and abdomen showed a diffuse infiltrating process in the right lung, with stenosis of the upper lobe and middle lobe bronchus, multiple pulmonary nodules on both sides and enlarged mediastinal lymph nodes, and a lymphangitis carcinomatosis in the right upper lobe, see Fig. 2. In addition, there was a suspect infiltration of the pericardium. Additionally, there were multiple cerebral metastases with a diameter of up to 18 mm, which were predominantly localized supratentorial. Furthermore, there were multiple bone lesions:

Fig. 2  Magnetic resonance examination (T2 STIR): Infiltration of the right lung with pleural effusion and multiple metastases in the left lung

2   Lung cancer in pregnancy

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The main finding was an extensive metastatic infestation of the second thoracic vertebral body with epidural infiltration and a consecutive narrowing of the spinal canal, as well as incipient tumorous changes in the spinous process of the third thoracic vertebra. Due to the high grade of the tumor infestation of the second thoracic vertebra, an immediate neurosurgical case conference was obtained. The MR findings indicated a threatening paraplegia in the case of further tumor progression. Small (up to a few mm in diameter) signal changes suggestive of metastases have been discovered in the first rib on the left, the right femoral head, the left ischial tuberosity and Os ileum, and in the sacrum on both sides. Uterus, placenta, and fetus appeared inconspicuous. An undifferentiated adenocarcinoma of the right lung with pulmonary, osseous, and cerebral metastases was diagnosed. The clinical and radiological staging revealed cT4N2M1b—Stage IV. After an extensive review and consultation with the attending gynecologists and specialists in prenatal medicine from the Women’s and Children’s Hospital Linz and a discussion regarding the toxicity of chemotherapy in pregnancy with the hemato-oncologists and as no conspicuous development of the fetus was present, the patient was administered a cycle of docetaxel/carboplatin (AUC5) on 6 June 2012. A neurosurgical evaluation because of vertebral metastatic disease (TH1–TH3) recommended no neurosurgical intervention as long as neurological symptoms remained absent and as long as the pregnancy was intact. However, palliative radiotherapy Th1–Th3 with 3000 cGy in 12 fractions was agreed to and was carried out in June 2012. Renewed prenatal control showed a normal development of the fetus, and after lung maturation with 2 × 12 mg Solu-Celestan, the patient delivered a healthy baby girl (1.441 g, 41 cm) by means of Cesarean section in the 31st week of gestation on 2 July 2012. Two days after delivery and weaning with Dostinex, therapy with gefitinib (Iressa ®) was started. At this point, a CT scan of the neck, abdomen, thorax, and pelvis including bone reconstruction was carried out. The results were unchanged compared with the initial MR examination 4 weeks ago with one exception: the tumor had considerably progressed in the upper thoracic spine. The second thoracic vertebra was completely destructed, collapsed, and showed anterolisthesis with consecutive compression of the spinal cord at this level, see Fig.  3. The adjacent vertebral bodies also showed a progressing tumor infestation. The neurologically asymptomatic patient was transferred to the neurosurgery department. A ventral corporectomy Th1/2 and anterior as well as posterior osteosynthesis C6/7 Th3/4 were performed on 6 July 2012. Under continued treatment with gefitinib, she was discharged from hospital on 13 July 2012. A restaging at the end of July showed that gefitinib treatment had caused dermatitis grade I-II. Except for slight pain in the spine, the patient was subjectively free

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Fig. 3  Computed tomography: Instabile fracture of the second thoracic vertebra with anterolisthesis and compression of the spinal cord

of symptoms. Regredient tumor markers in the lab were accompanied by a partial remission of the tumor shown in a thoracic CT examination (pulmonary primary lesion regressed from formerly 11 to 3.7  cm—which were not clearly distinguishable from atelectasis and tumor). The MR examination showed that cerebral metastases have also decreased in size (from 18 to 2–6 mm). A supplementary cerebral radiotherapy was rejected by the patient. In a follow-up control in October 2012, patchy peribronchial infiltrates in the right lower lobe were discovered, but these were declining under an antiinflammatory and antibiotic therapy. The tumor was found to be still in regression, see Fig.  4. The patient remained both clinically and radiologically stable under therapy with gefitinib. The child developed appropriately.

Lung cancer in pregnancy  

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case report Fig. 4  Computed tomography: Restaging July 2012 (left) compared with October 2012 (right): partial remission with shrinking of the tumor in the right upper lobe and inflammatory patchy infiltrates in the right lower lobe

A restaging in June 2013, 1 year after initial diagnosis, revealed slightly rising tumor markers in the lab (CEA), and on chest CT examination a low-grade progression in the right upper lobe and middle lobe, see Fig. 5. MR examination of the head and spinal column does not indicated progressive disease. Bronchoscopy showed narrowing of the middle lobe bronchus. The histological examination of specimen taken from this place indicated some single atypical cell complexes but no clear tumor invasion. At the end of July 2013, the patient was admitted to the pulmonary department due to a progressive deterioration of her general condition, and word finding difficulties and disorientation were among her neurological symptoms. The cerebral MR examination showed a newly emerged venous sinus thrombosis, the cerebral metastases remained unchanged. Lumbar puncture confirmed cells of an adenocarcinoma in the cerebrospinal fluid indicating carcinomatous meningitis. Intrathecal chemotherapy was discussed interdisciplinarily, but disconsidered due to the overall situation. In the presence of thoracic tumor progression and carcinomatous meningitis, the patient received one cycle of carboplatin/pemetrexed/bevacizumab on 2 August 2013. Supportive measures included parenteral nutrition. The

patient and her family members received supportive palliative care. In the absence of a clinical response to chemotherapy and the increasing deterioration of her general condition and neurological symptoms, best supportive care was eventually agreed to. The patient died at the age of 31 years, 17 months after diagnosis on 07 October 2013.

Discussion On average, cancer is diagnosed in 1 out of 1000–2000 pregnancies. However, the proportion of lung cancers is extremely low [1]. In Austria lung cancer in women has continued to increase over the past 3 decades from an annual rate of approximately 750–1500 [2]. The ratio of women to men has therefore shifted from 1:3.7 to 1:1.8. Our own patient records at the General Hospital in Linz, show that 1137 tracheo-bronchial carcinomas were newly diagnosed over the past 5 years. A total of 366 cases being women—according to a ratio of 366:771 or of 1:2.1. In all, 37 women (10.1 %) were younger than 50 years, and only two (0.55 %) were younger than 30 years. The coincidence of pregnancy and lung cancer remains extremely low under the age of 30.

Fig. 5  Computed tomography: Restaging March 2013 (left) compared with June 2013 (right): progressive disease in the right upper lobe

4   Lung cancer in pregnancy

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However, due to the increasing number of smoking women and the displacement of pregnancies to the third and fourth decade of life, we can expect a higher coincidence of lung cancer and pregnancy in the future. A review from Azim et al. [3] summarizes a total of 44 cases of lung cancer during pregnancy up until 2010. This overall summary shows an unfavorable outcome for the women after the birth of the child—less than a quarter survived more than a year. The majority already had metastases at the time of diagnosis. In most described cases, the child was delivered and then therapy commenced. In total, 8 of 42 patients received systemic treatment with normal fetal development during pregnancy. Massive tumor growth indicating an influence of estrogen and progesterone during pregnancy, is still the subject of investigations. In addition to the individual cases described of estrogen receptor-positive lung carcinomas [4], results of the Women’s Health Initiative trial published in the Lancet in 2009 [5] showed an influence of estrogen and progesterone in postmenopausal women on the mortality of lung cancer, but not on the incidence. A study of Nose et al. [6] detected in almost 50 % of women with adenocarcinoma of the lung, an increased expression of estrogen receptors α and β. In the objective situation of lung cancer in pregnancy, the estrogen and progesterone levels are expected to elevate during gestation. In the described patient, however, the tumor cells proved to be immunohistochemical estrogen and progesterone receptor negative. Hence, the influence of hormonal contraception for a period of 13 years appears to have been of minor importance. By determining the estrogen and progesterone receptor status in women with lung cancer, a possibility of an additional treatment option for patients with a positive receptor status may be opened up in the future. In a study of Tranyor et al. [7], 22 postmenopausal patients with non-small cell lung carcinoma were treated with the tyrosine-kinase inhibitor gefitinib 250 mg daily and the anti-estrogen fulvestrant 250 mg monthly. In case of > 60 % estrogen receptor positive cells, the average survival was extended from 21 to 65 weeks (compared with subjects with

Lung cancer in pregnancy.

In the 26th week of gestation, a 29-year-old pregnant office employee was referred to the pulmonary department of Linz General Hospital (AKH) under th...
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