A 19-Year-Old With Hemoptysis and Shortness of Breath

Case PresentationA 19-year-old woman with no medical history who did not use tobacco presented to the hospital with post-COVID-19 cough for 2 months and new onset of shortness of breath and blood-tinged sputum. She was initially treated empirically for community-acquired pneumonia because her chest radiograph showed a right upper lobe infiltrate. Further CT scan imaging revealed a right hilar lymph node conglomerate and extensive lymphadenopathy. The patient left to pursue care at a facility that accepted her insurance. Two weeks later, the patient presented for severe left-sided lower back pain, and she was found to have new complete left lower lobe collapse, likely because of extrinsic compression of the left lower lobe bronchus. She was treated for pain, and she left for insurance reasons. Two months later, the patient presented with progressive shortness of breath and hemoptysis and a 23-kg weight loss over the past 4 months. Because of the patient’s increasing medical needs, she was transferred to our institution, where she was admitted to the medical ICU. A 19-year-old woman with no medical history who did not use tobacco presented to the hospital with post-COVID-19 cough for 2 months and new onset of shortness of breath and blood-tinged sputum. She was initially treated empirically for community-acquired pneumonia because her chest radiograph showed a right upper lobe infiltrate. Further CT scan imaging revealed a right hilar lymph node conglomerate and extensive lymphadenopathy. The patient left to pursue care at a facility that accepted her insurance. Two weeks later, the patient presented for severe left-sided lower back pain, and she was found to have new complete left lower lobe collapse, likely because of extrinsic compression of the left lower lobe bronchus. She was treated for pain, and she left for insurance reasons. Two months later, the patient presented with progressive shortness of breath and hemoptysis and a 23-kg weight loss over the past 4 months. Because of the patient’s increasing medical needs, she was transferred to our institution, where she was admitted to the medical ICU. In the medical ICU, the patient was found to have a temperature of 35 °C, heart rate of 101 beats/min, and respiratory rate of 27 breaths/min. She had an oxygen saturation of 100% on 100% Fio2 of high-flow nasal cannula at 25 L/min. On examination, the patient had decreased breath sounds on the left side, but she had no wheezes or crackles bilaterally. She had normal findings on cardiac, abdomen, neurologic, and skin examinations. During this admission, the patient was found to have leukocytosis (16.52 K/μL) with a neutrophil predominance (79.4%), thrombocytosis (420 K/μL), and normocytic anemia (hemoglobin 5.5 g/dL, mean corpuscular volume 81 fL, iron 13 μg/dL, total iron binding capacity 131 μg/dL, ferritin 764 ng/mL). The patient also had elevated lactate dehydrogenase (269 International Units/L), aspartate aminotransferase (88 units/L), gamma-glutamyl transferase (280 units/L), and alkaline phosphatase (203 units/L). Microbiology workup results for bacterial cultures (including acid-fast cultures, mycoplasma pneumonia, Chlamydia pneumoniae, and legionella), viral cultures (influenza, parainfluenza, rhinovirus/enterovirus, COVID-19, respiratory syncytial virus), and fungal cultures (including Candida species and Pneumocystis jirovecii) were negative. Chest radiograph and CT chest scans showed a significant increase in size of the right upper lung opacity, extensive lymphadenopathy in the lower neck and chest, complete occlusion of the left mainstem bronchus secondary to lymphadenopathy, and new complete atelectasis of the left lung with moderate pleural effusion (Figs 1, 2).Figure 2Chest CT scan with contrast showing opacity in the anteromedial right upper lung, metastatic lymphadenopathy, occlusion of the left mainstem bronchus, and consolidation/atelectasis of the left lung.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Pathology showed poorly differentiated solid epithelial neoplastic cells (Fig 3A) with mucicarmine staining positive for mucin (Fig 3B). Immunohistochemical staining showed positive nuclear staining for transcription termination factor 1 (Fig 4A), cytoplasmic staining for anaplastic lymphoma kinase (ALK) (Fig 4B), and programmed death ligand 1 (PD-L1) staining in a membranous pattern (Fig 4C). Fluorescence in situ hybridization studies were negative for receptor tyrosine kinase ROS proto-oncogene 1 (ROS1) or RET proto-oncogene (RET) rearrangement (Fig 5).Figure 4A-C, Immunohistochemical staining results; brown staining is positive: (A) positive nuclear staining for transcription termination factor-1, consistent with adenocarcinoma of pulmonary origin; (B) positive cytoplasmic staining for anaplastic lymphoma kinase; and (C) positive programmed death ligand 1 staining in a membranous pattern (original magnification at ×400).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 5Fluorescence in situ hybridization demonstrating no evidence of receptor tyrosine kinases ROS proto-oncogene 1 (ROS1) or RET proto-oncogene (RET) rearrangement.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The patient underwent bronchoscopy for debridement of the occlusion with cryotherapy, left mainstem metal stent placement, and biopsy and resection of the right upper lobe endobronchial lesion with periprocedural extracorporeal membrane oxygenation support (Fig 6). The course was complicated by subsequent ARDS, and she remained intubated in the ICU for 1 week. What is the diagnosis? Diagnosis: ALK+ primary lung adenocarcinoma This case highlights multiple unique aspects of lung cancer presentation in young people, particularly the aggressiveness of disease in terms of metastasis and local spread, and responsiveness to treatment. Several studies report similar findings in the common clinical presentations of lung cancer in younger patients. A systematic review of English-language studies of adenocarcinoma in pediatric and adolescent populations found that the most common presenting symptoms were largely respiratory with chest pain (19.4%), failure to respond to antibiotics (19.4%), and hemoptysis (13.9%). Outside of these, other common presenting symptoms found were related to metastatic disease, including headache, altered mental status, abdominal pain, and back pain (25.45%). In addition to respiratory symptoms, the patient initially presented with hemoptysis, which has been well documented in adult populations to be the strongest predictor for lung cancer diagnosis. In fact, current guidelines by the National Institute for Health and Care Excellence in the United Kingdom, the Scottish Intercollegiate Guidelines Network, and the New Zealand Guidelines Group regard hemoptysis as an alarm sign that should prompt further investigation for possible lung cancer. Similarly, other studies on adult patients point to loss of appetite, weight loss, hoarseness, and thrombocytosis as other symptoms having high positive predictive value for lung cancer. At various points in her disease course, the patient presented with multiple of these symptoms, including 23-kg weight loss, hoarseness, and thrombocytosis. Compared with older patients, younger patients with lung cancer are more likely to present with metastatic disease, possibly because of delayed diagnosis because of nonspecific presenting symptoms and low clinical suspicion. One study of patients aged ≤ 40 years with non-small cell cancer found that the median number of days from initial presentation to tissue diagnosis ranged from 1 to 1,076 days, with a median number of 61 days. This patient had approximately 22 days between her initial presentation to informal tissue diagnosis, but she did not receive a formal diagnosis and therefore was not treated until 65 days, at which point her disease had progressed to include metastatic disease to the liver and brain. Liver metastases in children and adolescents are so rare that the exact incidence of them remains unknown. Brain metastases in children, adolescents, and young adults with solid primary tumors are also incredibly rare, especially for those presenting with primary lung cancer. A study of lung cancer in young adults aged < 35 years found the most common metastatic presentation sites to be pleura (38.71%), bone (35.48%), lung (25.81%), liver (12.90%), and brain (9.68%). As the patient’s tumor progressed, it displayed a characteristic well known to Pancoast tumors and the patient subsequently developed Horner syndrome, characterized by ptosis and miosis of the left eye, during her hospital course because of compression of the stellate ganglion. The most common tumors causing Horner syndrome in pediatric populations are neuroblastomas and rhabdomyosarcomas, whereas in adult populations, there was found to be a broader range of carcinomas, including those of neuroendocrine, thyroid, lymphoma, breast, and lung origin. Interestingly, one study found Horner syndrome to have a peak incidence at 50 to 54 years of age in the adult population and 0 to 4 years of age in the pediatric population, which further highlights the rarity of this patient’s clinical presentation given her age of 19 years. Molecular testing for somatic mutations is recommended for confirmed adenocarcinomas according to adult lung cancer guidelines, looking for EGFR, KRAS, BRAF, ROS-1, and ALK. Gene rearrangements of ALK result in constitutive activation and ALK-driven tumor formation, and have been show in various other pediatric cancers such as glioma, Ewing sarcoma, and neuroblastoma, in addition to lung adenocarcinoma more recently. Interestingly, patients with ALK-positive lung adenocarcinoma present at a younger age, with studies showing that TNM stages inversely correlate with the age at diagnosis in ALK-positive lung cancer, specifically with increased frequency of brain and liver metastasis, as was seen in this patient. ALK-positive tumors can be targeted with ALK inhibitors (eg, crizotinib) and the newer next-generation drugs ceritinib and alectinib. These newer targeted biological agents have shown significantly superior efficacy compared with typical treatment with chemotherapy. Current adult trials show that for treatment of ALK-positive non-small cell cancer, alectinib is superior in efficacy (as measured by overall response rate, progression-free survival, and partial response) and lower in toxicity and adverse reactions in comparison with crizotinib. However, although crizotinib has been proven to show efficacy and safety for treating ALK+ solid tumors in pediatric populations and ceritinib has been proven to show efficacy and safety for treating other ALK+ malignancies in pediatric populations, there are no established data supporting alectinib’s safety or efficacy in younger patients. One case report does, however, show the efficacy and safety of use of adult dose alectinib in stage IVB ALK+ cancer in a 14-year-old girl showing complete metabolic remission for 9 months. Immediately after cancer pathology results returned, the patient was started on alectinib and a stent mucolytic regimen, rapidly weaned off of pressors, extubated, and downgraded to the floor. On physical examination on the floor, she was found to have Horner syndrome and superior vena cava syndrome from extrinsic compression from her malignancy. Further staging with MRI scan and CT scan demonstrated metastases to her right cerebral caudate lobe and posterolateral right hepatic lobe (Figs 7, 8). The patient was started on radiation treatment, but after receiving two radiation fractions to the mediastinal lung mass, the decision was made to discontinue radiation and continue with only chemotherapy because of the rapid improvement in her symptoms with chemotherapy.Figure 8CT scan showing a vague hypoenhancing 20-mm right hepatic lesion, suspicious for liver metastasis.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Three months after initiating alectinib in July, this patient was nearly asymptomatic, with a fluorodeoxyglucose PET scan showing improvement including significantly decreased although still persistent lung consolidations, thoracic and abdominal lymphadenopathy, and nodal metastases and resolution of the bilateral pleural effusion. 1.Given the aggressive nature of these malignancies, early recognition of symptoms that should raise suspicion for lung cancer in young patients is critical for slowing or preventing progression to widespread disease (eg, distant metastases, Horner syndrome, superior vena cava syndrome).2.Physicians should recognize the importance of molecular sequencing to better guide treatment options for these tumors.3.Alectinib demonstrated superiority in efficacy and adverse reactions for treatment of ALK+ adenocarcinoma in adult trials. However, there are currently no established data supporting alectinib’s safety or efficacy in younger patients. None declared. Other contributions: We thank Wayne W. Grody, MD, PhD, and Michael C. Fishbein, MD, for helping to obtain the cytogenetics and pathology information and images. CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.